Dosage forms comprising a CETP inhibitor and an HMG-CoA reductase inhibitor

ABSTRACT

A dosage form comprises (1) a solid amorphous dispersion comprising a cholesteryl ester transfer protein inhibitor and a neutral or neutralized acidic polymer and (2) an HMG-CoA reductase inhibitor. The dosage form provides improved chemical stability of the HMG-CoA reductase inhibitor.

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of priority of provisionalPatent Application Serial No. 60/435,298 filed Dec. 20, 2002, which isincorporated herein by reference in its entirety for all purposes.

BACKGROUND

[0002] The present invention relates to a dosage form comprising: (1) asolid amorphous dispersion comprising a cholesteryl ester transferprotein (CETP) inhibitor and a neutral or neutralizedconcentration-enhancing polymer; and (2) an acid-sensitive HMG-CoAreductase inhibitor.

[0003] It is well known that inhibitors of3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), animportant enzyme catalyzing the intracellular synthesis of cholesterol,will bring about reduced levels of blood cholesterol, especially interms of the low density lipoprotein (LDL) form of cholesterol.Therefore, HMG-CoA reductase enzyme inhibitors are consideredpotentially useful as hypocholesterolemic or hypolipidemic agents.

[0004] CETP inhibitors are another class of compounds that are capableof modulating levels of blood cholesterol such as by raising highdensity lipoprotein (HDL) cholesterol and lowering LDL cholesterol. CETPinhibitors have extremely low aqueous solubility. Accordingly, CETPinhibitors must be formulated so as to be capable of providing goodbioavailability. One method for increasing the bioavailability of a CETPinhibitor is to form a solid amorphous dispersion of the drug and aconcentration-enhancing polymer. See, e.g., WO02/11710 A2.

[0005] It is well known that a combination therapy of a CETP inhibitorand an HMG-CoA reductase inhibitor may be used to treat elevated LDLcholesterol and low HDL cholesterol levels. For example, WO02/13797 A2relates to pharmaceutical combinations of cholesteryl ester transferprotein inhibitors and atorvastatin. The application discloses that thecompounds may be generally administered separately or together, with apharmaceutically acceptable carrier, vehicle or diluent. The compoundsmay be administered individually or together in any conventional oral,parenteral or transdermal dosage form. For oral administration, thecomposition may take the form of solutions, suspensions, tablets, pills,capsules, powders and the like.

[0006] DeNinno et al., U.S. Pat. No. 6,310,075 B1 relates to CETPinhibitors, pharmaceutical compositions containing such inhibitors andthe use of such inhibitors. DeNinno et al. disclose a pharmaceuticalcombination composition comprising a CETP inhibitor and an HMG-CoAreductase inhibitor. DeNinno disclose that the compounds of theinvention may be administered in the form of a pharmaceuticalcomposition comprising at least one of the compounds, together with apharmaceutically acceptable vehicle, diluent, or carrier. For oraladministration a pharmaceutical composition can take the form ofsolutions, suspensions, tablets, pills, capsules, powders and the like.Similarly, DeNinno et al., U.S. Pat. No. 6,197,786 B1 disclosepharmaceutical combinations comprising CETP inhibitors and HMG-CoAreductase inhibitors.

[0007] WO 00/38722 discloses combinations of CETP inhibitors and HMG-CoAreductase inhibitors for cardiovascular indications. The pharmaceuticalcompositions include those suitable for oral, rectal, topical, buccal,and parenteral administration. The application discloses solid dosageforms for oral administration including capsules, tablets, pills,powders, gel caps and granules.

[0008] Schmeck et al., U.S. Pat. No. 5,932,587 disclose another class ofCETP inhibitors. Schmeck et al. disclose that the CETP inhibitors may beused in combination with certain HMG-CoA reductase inhibitors such asstatins, including atorvastatin.

[0009] However, while it is desired to combine the CETP inhibitor and anHMG-CoA reductase inhibitor into a single dosage form, combining a CETPinhibitor and an HMG-CoA reductase inhibitor into a single dosage formpresents a number of potential problems. Some HMG-CoA reductaseinhibitor compounds are unstable in that they are susceptible to heat,moisture, low pH environment, and light. Some HMG-CoA reductaseinhibitors, such as atorvastatin, pravastatin, fluvastatin,rosuvastatin, and cerivastatin are in the form of hydroxy acids thatwill degrade to a lactone in an acidic environment. Other HMG-CoAreductase inhibitors, such as lovastatin and simvastatin, containsubstituents that readily degrade in an acidic environment. Whenpackaged in the form of tablets, powders, granules, or within capsules,the HMG-CoA reductase inhibitor may be further destabilized by contactwith the molecular moieties of other components of the dosage form.Since pharmaceutical dosage form components such as binders, diluents,antiadherents, surfactants and the like may adversely interact with theactive ingredient compound, a stabilizing means may be required foreffective pharmaceutical dosages. For example, U.S. Pat. No. 6,126,971discloses the addition of a stabilizing agent such as calcium carbonateto stabilize the HMG-CoA reductase inhibitor atorvastatin calcium.Nevertheless, the means for stabilizing the HMG-CoA reductase inhibitormust also allow solubilization of the CETP inhibitor.

[0010] Accordingly, what is desired is a dosage form containing a CETPinhibitor and an HMG-CoA reductase inhibitor that stabilizes the HMG-CoAreductase inhibitor and that provides good bioavailability for the CETPinhibitor.

SUMMARY OF THE INVENTION

[0011] The present invention overcomes the drawbacks of the prior art byproviding a unitary dosage form comprising (1) a solid amorphousdispersion comprising a CETP inhibitor and a neutral or a neutralizedacidic concentration-enhancing polymer and (2) an HMG-CoA reductaseinhibitor.

[0012] In one aspect, a unitary dosage form comprises (1) a solidamorphous dispersion comprising a CETP inhibitor and a neutralconcentration-enhancing polymer, and (2) an HMG-CoA reductase inhibitor.The concentration-enhancing polymer chosen to form the solid amorphousdispersion should be neutral, so that the polymer does not cause adversechemical degradation of the HMG-CoA reductase inhibitor. The HMG-CoAreductase-inhibitor in the resulting unitary dosage form has improvedchemical stability when compared to a control dosage form where theconcentration-enhancing polymer in the control dosage form is the acidicpolymer hydroxypropyl methyl cellulose acetate succinate (HPMCAS).

[0013] In another aspect, the unitary dosage form comprises (1) a solidamorphous dispersion comprising a CETP inhibitor and a neutralizedacidic concentration-enhancing polymer, and (2) an HMG-CoA reductaseinhibitor. The concentration-enhancing polymer chosen to form the solidamorphous dispersion should be an acidic polymer wherein a sufficientquantity of the acidic groups in the polymer have been neutralized, sothat the polymer does not cause adverse chemical degradation of theHMG-CoA reductase inhibitor. The HMG-CoA reductase inhibitor in theresulting unitary dosage form has improved chemical stability whencompared to a control dosage form where the concentration-enhancingpolymer in the control dosage form is the unneutralized acidic polymer.

[0014] By “unitary dosage form” is meant a single dosage form containingboth the CETP inhibitor and HMG-CoA reductase inhibitor so that,following administration of the unitary dosage form to a useenvironment, both the CETP inhibitor and HMG-CoA reductase inhibitor aredelivered to the use environment. The term “unitary dosage form”includes a single tablet, caplet, pill, capsule, powder, or a kitcomprising one or more tablets, caplets, pills, capsules, sachets,powders, or solutions intended to be taken together.

[0015] Reference to a “use environment” can either mean in vivo fluids,such as the GI tract, subdermal, intranasal, buccal, intrathecal,ocular, intraaural, subcutaneous spaces, vaginal tract, arterial andvenous blood vessels, pulmonary tract or intramuscular tissue of ananimal, such as a mammal and particularly a human, or the in vitroenvironment of a test solution, such as phosphate buffered saline (PBS)or a Model Fasted Duodenal (MFD) solution. An appropriate PBS solutionis an aqueous solution comprising 20 mM sodium phosphate (Na₂HPO₄), 47mM potassium phosphate (KH₂PO₄), 87 mM NaCl, and 0.2 mM KCl, adjusted topH 6.5 with NaOH. An appropriate MFD solution is the same PBS solutionwherein additionally is present 7.3 mM sodium taurocholic acid and 1.4mM of 1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine.

[0016] “Administration” to a use environment means, where the in vivouse environment is the GI tract, delivery by ingestion or swallowing orother such means to deliver the drugs. One skilled in the art willunderstand that “administration” to other in vivo use environments meanscontacting the use environment with the composition of the inventionusing methods known in the art. See for example, Remington: The Scienceand Practice of Pharmacy, 20^(th) Edition (2000). Where the useenvironment is in vitro, “administration” refers to placement ordelivery of the dosage form to the in vitro test medium. Where releaseof drug into the stomach is not desired but release of the drug in theduodenum or small intestine is desired, the use environment may also bethe duodenum or small intestine. In such cases, “introduction” to a useenvironment is that point in time when the dosage form leaves thestomach and enters the duodenum.

[0017] The inventors have found that the bioavailability of CETPinhibitors may be substantially improved by forming a solid amorphousdispersion of the CETP inhibitor and a concentration-enhancing polymer.The administration of the CETP inhibitor in the form of a solidamorphous dispersion containing a concentration-enhancing polymersubstantially increases the concentration of dissolved CETP inhibitor inthe use environment relative to administration of the CETP inhibitor incrystalline form. In turn, this enhanced concentration of dissolved CETPinhibitor results in an increase in the bioavailability of the CETPinhibitor as indicated by an increase in the area under theconcentration versus time curve (AUC) in the blood.

[0018] However, when an HMG-CoA reductase inhibitor is mixed directlywith a solid amorphous dispersion comprising the CETP inhibitor and theacidic concentration-enhancing polymer HPMCAS and then granulated in atableting formulation, the inventors observe chemical degradation of theHMG-CoA reductase inhibitor that is greater than that observed for theHMG-CoA reductase inhibitor alone. The inventors solved the chemicaldegradation problem by replacing the acidic concentration-enhancingpolymer with a neutral or neutralized acidic concentration-enhancingpolymer. The inventors believe that the chemical degradation of the HMGCo-A reductase inhibitor was caused either directly by the acidicconcentration-enhancing polymer or indirectly by migration of the acidto the surface of the HMG-CoA reductase inhibitor. The inventors foundthat the chemical stability of the HMG-CoA reductase inhibitor in theunitary dosage form could be improved by replacing the acidic polymerwith a neutral or neutralized acidic polymer. In addition, the resultingsolid amorphous dispersion provides concentration enhancement in a useenvironment for the CETP inhibitor.

[0019] The foregoing and other objectives, features, and advantages ofthe invention will be more readily understood upon consideration of thefollowing detailed description of the invention.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0020] The present invention combines a CETP inhibitor and an HMG-CoAreductase inhibitor in a unitary dosage form. The CETP inhibitor is inthe form of a solid amorphous dispersion comprising a neutral orneutralized acidic concentration-enhancing polymer. Unitary dosageforms, solid amorphous dispersions, neutral and neutralizedconcentration-enhancing polymers, drugs, excipients, and methods forforming the dosage forms are discussed in more detail below.

SOLID AMORPHOUS DISPERSIONS OF CETP INHIBITORS

[0021] The CETP inhibitor and concentration-enhancing polymer arecombined and formed into a solid amorphous dispersion. By solidamorphous dispersion is meant a solid material in which at least aportion of the CETP inhibitor is in the amorphous form and dispersed inthe polymer. Preferably, at least a major portion of the CETP inhibitorin the solid amorphous dispersion is amorphous. By “amorphous” is meantsimply that the CETP inhibitor is in a non-crystalline state. As usedherein, the term “a major portion” of the CETP inhibitor means that atleast 60 wt % of the CETP inhibitor in the solid amorphous dispersion isin the amorphous form, rather than the crystalline form. Preferably, theCETP inhibitor in the solid amorphous dispersion is substantiallyamorphous. As used herein, “substantially amorphous” means that theamount of CEPT inhibitor in crystalline form does not exceed about 25 wt%. More preferably, the CETP inhibitor in the solid amorphous dispersionis “almost completely amorphous,” meaning that the amount of CETPinhibitor in the crystalline form does not exceed about 10 wt %. Amountsof crystalline CETP inhibitor may be measured by Powder X-RayDiffraction (PXRD), Scanning Electron Microscope (SEM) analysis,differential scanning calorimetry (DSC), or any other standardquantitative measurement.

[0022] The solid amorphous dispersion may contain from about 1 to about80 wt % CETP inhibitor, depending on the dose of the CETP inhibitor andthe effectiveness of the concentration-enhancing polymer. Enhancement ofaqueous CETP inhibitor concentrations and relative bioavailability aretypically best at low CETP inhibitor levels, typically less than about25 to about 40 wt %. However, due to the practical limit of the dosageform size, higher CETP inhibitor levels may be preferred and in manycases perform well.

[0023] The amorphous CETP inhibitor can exist within the solid amorphousdispersion in relatively pure amorphous drug domains or regions, as asolid solution of drug homogeneously distributed throughout the polymeror any combination of these states or those states that lie intermediatebetween them. The solid amorphous dispersion is preferably substantiallyhomogeneous so that the amorphous CETP inhibitor is dispersed ashomogeneously as possible throughout the polymer. As used herein,“substantially homogeneous” means that the fraction of CETP inhibitorthat is present in relatively pure amorphous drug domains or regionswithin the solid amorphous dispersion is relatively small, on the orderof less than 20 wt %, and preferably less than 10 wt % of the totalamount of drug. Solid amorphous dispersions that are substantiallyhomogeneous generally are more physically stable and have improvedconcentration-enhancing properties and, in turn, improvedbioavailability, relative to nonhomogeneous dispersions.

[0024] In cases where the CETP inhibitor and the polymer have glasstransition temperatures sufficiently far apart (greater than about 20°C.), the fraction of drug that is present in relatively pure amorphousdrug domains or regions within the solid amorphous dispersion can bedetermined by examining the glass transition temperature (T_(g)) of thesolid amorphous dispersion. T_(g) as used herein is the characteristictemperature where a glassy material, upon gradual heating, undergoes arelatively rapid (e.g., in 10 to 100 seconds) physical change from aglassy state to a rubbery state. The T_(g) of an amorphous material suchas a polymer, drug, or dispersion can be measured by several techniques,including by a dynamic mechanical analyzer (DMA), a dilatometer, adielectric analyzer, and by DSC. The exact values measured by eachtechnique can vary somewhat, but usually fall within 100 to 30° C. ofeach other. When the solid amorphous dispersion exhibits a single T_(g),the amount of CETP inhibitor in pure amorphous drug domains or regionsin the solid amorphous dispersion is generally has less than about 10 wt%, confirming that the solid amorphous dispersion is substantiallyhomogeneous. This is in contrast to a simple physical mixture of pureamorphous drug particles and pure amorphous polymer particles whichgenerally display two distinct T_(g)s, one being that of the drug andone that of the polymer. For a solid amorphous dispersion that exhibitstwo distinct T_(g)s, one in the proximity of the drug T_(g) and one ofthe remaining drug/polymer dispersion, at least a portion of the drug ispresent in relatively pure amorphous domains. The amount of CETPinhibitor present in relatively pure amorphous drug domains or regionsmay be determined by first preparing calibration standards ofsubstantially homogeneous dispersions to determine T_(g) of the solidamorphous dispersion versus drug loading in the dispersion. From thesecalibration data and the T_(g) of the drug/polymer dispersion, thefraction of CETP inhibitor in relatively pure amorphous drug domains orregions can be determined. Alternatively, the amount of CETP inhibitorpresent in relatively pure amorphous drug domains or regions may bedetermined by comparing the magnitude of the heat capacity for thetransition in the proximity of the drug T_(g) with calibration standardsconsisting essentially of a physical mixture of amorphous drug andpolymer. In either case, a solid amorphous dispersion is considered tobe substantially homogeneous if the fraction of CETP inhibitor that ispresent in relatively pure amorphous drug domains or regions within thesolid amorphous dispersion is less than 20 wt %, and preferably lessthan 10 wt % of the total amount of CETP inhibitor.

CONCENTRATION ENHANCING POLYMERS

[0025] The concentration-enhancing polymers suitable for use in thesolid amorphous dispersions of the present invention should be inert, inthe sense that they do not chemically react with the CETP inhibitor inan adverse manner when present in the composition. The polymer shouldalso have an aqueous-solubility of at least 0.1 mg/mL over at least aportion of the pH range of 1-8. While specific polymers are discussed asbeing suitable for use in the compositions of the present invention,blends of such polymers may also be suitable. Thus the term “polymer” isintended to include blends of polymers in addition to a single speciesof polymer.

NEUTRAL POLYMERS

[0026] One class of concentration-enhancing polymers consists of“neutral polymers,” meaning that the polymer possesses substantially noacidic functional groups. By “substantially no acidic functional groups”is meant that the number of acidic groups covalently attached to thepolymer is less than about

[0027] 0.05 milliequivalents per gram of polymer. Preferably, the numberis less than about 0.02 millequivalents per gram of polymer. By “acidicgroups” is meant functional groups that, when attached to the polymer,have pK_(a) values in a humid or aqueous environment of about 5 or less.Preferably, the pK_(a) value of the functional groups on the neutralpolymer is greater than about 6. Thus, the neutral polymers may containionic groups as long as the groups are not acidic.

[0028] The neutral concentration-enhancing polymer may be cellulosic ornon-cellulosic. A preferred class of neutral cellulosic polymers arethose with at least one ester- and/or ether-linked substituent in whichthe polymer has a degree of substitution of at least 0.02 for eachsubstituent. It should be noted that in the polymer nomenclature usedherein, ether-linked substituents are recited prior to “cellulose” asthe moiety attached to the ether group; for example, “methyl cellulose”has a methyl moiety ether-linked to the polymer. In contrast,ester-linked substituents are recited after “cellulose” as thecarboxylate; for example, “cellulose acetate” has an acetate moietyester-linked to the polymer.

[0029] It should also be noted that a polymer name such as “celluloseacetate butyrate” refers to any of the family of cellulosic polymersthat have acetate and butyrate groups attached via ester linkages to asignificant fraction of the cellulosic polymer's hydroxyl groups.Generally, the degree of substitution of each substituent group canrange from about 0.02 to 2.9 as long as the other criteria of thepolymer are met. “Degree of substitution” refers to the average numberof the three hydroxyls per saccharide repeat unit on the cellulose chainthat have been substituted. For example, if all of the hydroxyls on thecellulose chain have been butyrate substituted, the butyrate degree ofsubstitution is 3. Also included within each polymer family type arecellulosic polymers that have additional substituents added inrelatively small amounts that do not substantially alter the performanceof the polymer.

[0030] Polymer substituents may be either non-ionizable or ionizable;however, the ionizable groups may not be acidic groups. Exemplaryether-linked non-ionizable substituents include: alkyl groups, such asmethyl, ethyl, propyl, butyl, etc.; hydroxy alkyl groups such ashydroxymethyl, hydroxyethyl, hydroxypropyl, etc.; and aryl groups suchas phenyl. Exemplary ester-linked non-ionizable groups include: alkylategroups, such as acetate, propionate, butyrate, etc.; and arylate groupssuch as phenylate. However, when ester-linked non-ionizable groups areincluded, the polymer may need to include a sufficient amount of ahydrophilic substituent so that the polymer has at least some watersolubility at any physiologically relevant pH of from 1 to 8. In thecase of ionizable neutral polymers, such hydrophilic substituents mayconsist of non-acidic ionizable groups such as amino-functionalizedgroups or phenolate groups. In the case of non-ionizable neutralpolymers, such hydrophilic groups are non-ionizable substituents such asalcohol, ether or ester groups.

[0031] Exemplary neutral non-ionizable cellulosic polymers that may beused to form the solid amorphous dispersion include: hydroxypropylmethyl cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropylcellulose, methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethylcellulose acetate, hydroxyethyl ethyl cellulose, and hydroxyethylcellulose.

[0032] Exemplary neutral, but ionizable cellulosic polymers, includeaminoethyl cellulose, aminoethyl cellulose acetate, hydroxypropyl aminoethyl cellulose and hydroxybenzyl cellulose.

[0033] Another class of neutral concentration-enhancing polymers isnon-cellulosic, neutral polymers. Such polymers may be eithernon-ionizable or ionizable. Exemplary non-ionizable, neutral polymersinclude vinyl polymers and copolymers having substituents of hydroxyl,alkylacyloxy, and cyclicamido. Exemplary non-cellulosic, neutralpolymers include hydroxyethyl methacrylate, polyvinylhydroxyethyl ether,polyethylene glycol, and polyoxyethylene-polyoxypropylene blockcopolymers also known as poloxamers.

[0034] Exemplary ionizable neutral polymers include amine-functionalizedpolyacrylates and polymethacrylates, some of which are also sold asEUDRAGITS manufactured by Rohm Tech Inc., and neutral proteins.

[0035] A preferred subset of neutral polymers are those that aregenerally amphiphilic in that they possess substituents that arerelatively hydrophobic and substituents that are relatively hydrophilic.Amphiphilic cellulosics may be prepared by substituting the cellulose atany or all of the 3 hydroxyl substituents present on each sacchariderepeat unit with at least one relatively hydrophobic substituent.Hydrophobic substituents may be essentially any substituent that, ifsubstituted to a high enough level or degree of substitution, can renderthe cellulosic polymer essentially aqueous insoluble. Hydrophilicregions of the polymer can be either those portions that are relativelyunsubstituted, since the unsubstituted hydroxyls are themselvesrelatively hydrophilic, or those regions that are substituted withhydrophilic substituents. Examples of hydrophobic substituents includeether-linked alkyl groups such as methyl, ethyl, propyl, butyl, etc.; orester-linked alkyl groups such as acetate, propionate, butyrate, etc.;and ether- and/or ester-linked aryl groups such as phenyl, benzoate, orphenylate. As discussed above, hydrophilic substituents may consist ofnon-acidic ionizable groups such as amino-functionalized groups orphenolate groups. In the case of non-ionizable neutralconcentration-enhancing polymers, such hydrophilic groups arenon-ionizable substituents such as alcohol, ether or ester groups.

[0036] Exemplary amphiphilic polymers include non-ionizable cellulosicssuch as hydroxypropyl methyl cellulose, hydroxyethyl methyl celluloseand hydroxyethyl cellulose acetate; non-acidic ionizable cellulosicssuch as amino ethyl cellulose acetate and hydroxybenzyl cellulose; andnon-ionizable non-cellulosics such as polyvinylpyrrolidone,ethylene/vinyl alcohol copolymers and polyoxyethylene-polyoxypropyleneblock copolymers (also referred to as poloxamers); and ionizablenon-cellulosics such as amine-functionalized polyacrylates andpolymethacrylates.

[0037] A preferred class of neutral non-cellulosic polymers arecomprised of vinyl copolymers of a hydrophilic, hydroxyl-containingrepeat unit and a hydrophobic, alkyl- or aryl-containing repeat unit.Such neutral vinyl copolymers are termed. “amphiphilichydroxyl-functional vinyl copolymers.” Amphiphilic hydroxyl-functionalvinyl copolymers are exceptional in that they are both non-ionic andyet, surprisingly, when used as dispersion polymers for low-solubilitydrugs, yield solid amorphous dispersions that provide high levels ofdrug concentration enhancement when dosed to an aqueous environment ofuse. Such polymers may be used with any low-solubility drug, and notsimply acid-sensitive drugs.

[0038] The preferred copolymers have the general structure:

[0039] where A and B represent “hydrophilic, hydroxyl-containing” and“hydrophobic” substituents, respectively, and n and m represent theaverage number of hydrophilic vinyl repeat units and average number ofhydrophobic vinyl repeat units respectively per polymer molecule.Copolymers may be block copolymers, random copolymers or they may havestructures anywhere between these two extremes. The sum of n and m isgenerally from about 50 to about 20,000 and therefore the polymers havemolecular weights from about 2,500 to about 1,000,000 daltons.

[0040] The hydrophilic, hydroxyl-containing repeat units, “A,” maysimply be hydroxyl (—OH) or it may be any short-chain, 1 to 6 carbon,alkyl with one or more hydroxyls attached thereto. Thehydroxyl-substituted alkyl may be attached to the vinyl backbone viacarbon-carbon or ether linkages. Thus, exemplary “A” structures include,in addition to hydroxyl itself, hydroxymethyl, hydroxyethyl,hydroxypropyl, hydroxymethoxy, hydroxyethoxy and hydroxypropoxy.

[0041] The hydrophobic substituent, “B,” may simply be: hydrogen (—H),in which case the hydrophobic repeat unit is ethylene; an alkyl or arylsubstituent with up to 12 carbons attached via a carbon-carbon bond suchas methyl, ethyl or phenyl; an alkyl or aryl substituent with up to 12carbons attached via an ether linkage such as methoxy, ethoxy orphenoxy; an alkyl or aryl substituent with up to 12 carbons attached viaan ester linkage such as acetate, propionate, butyrate or benzoate. Theamphiphilic hydroxyl-functional vinyl copolymers of the presentinvention may be synthesized by any conventional method used to preparesubstituted vinyl copolymers. Some substituted vinyl copolymers such aspolyvinyl alcohol/polyvinyl acetate are well known and commerciallyavailable.

[0042] Such polymers are more fully disclosed in commonly assignedpending patent application Ser. No. 60/300,255, filed Jun. 22, 2001,herein incorporated by reference.

NEUTRALIZED ACIDIC POLYMERS

[0043] Another class of polymers suitable for use with the solidamorphous dispersions of the present invention consists of neutralizedacidic polymers. By “acidic polymer” is meant any polymer that possessesa significant number of acidic moieties. In general, a significantnumber of acidic moieties would be greater than or equal to about 0.05milliequivalents of acidic moieties per gram of polymer. “Acidicmoieties” include any functional groups that are sufficiently acidicthat, in contact with or dissolved in water, can at least partiallydonate a hydrogen cation to water and thus increase the hydrogen-ionconcentration. This definition includes any functional group or“substituent,” as it is termed when the functional group is covalentlyattached to a polymer, that has a pK_(a) of less than about 10. Here,the term pK_(a) is used in its traditional form, the pK_(a) being thenegative logarithm of the acid ionization constant. The pK_(a) will beinfluenced by such factors as solvent, temperature, water content, andionic strength of the media or matrix in which the acid resides. Unlessotherwise noted, the pK_(a) is assumed to be measured in distilled waterat 25° C. Since in general, the more acidic the polymer the more usefulthe invention, the invention is preferred for polymers with functionalgroups with pK_(a)s of less than about 7, and even more preferred withpK_(a)s of less than about 6. Exemplary classes of functional groupsthat are included in the above description include carboxylic acids,thiocarboxylic acids, phosphates, phenolic groups, and sulfonates. Suchfunctional groups may make up the primary structure of the polymer suchas for polyacrylic acid, but more generally are covalently attached tothe backbone of the parent polymer and thus are termed “substituents.”

[0044] By “neutralized acidic polymer” is meant any acidic polymer forwhich a significant fraction of the “acidic moieties” or “acidicsubstituents” have been “neutralized”; that is, exist in theirdeprotonated form. The “degree of neutralization,” α, of a polymersubstituted with monoprotic acids (such as carboxylic acids) is definedas the fraction of the acidic moieties on the polymer that have beenneutralized; that is, deprotonated by a base. The degree to which theacidic moieties on the polymer are neutralized by the base is dependenton (1) the ratio of the number of milliequivalents of base per gram ofpolymer divided by the number of milliequivalents of acidic moieties pergram of polymer and (2) the relative pK_(a)s of the base and the acidicpolymer. When the pK_(a) of the base is much higher than the pK_(a) ofthe acidic moieties of the acidic polymer (that is, the ratio of thepK_(a) of the base to the pK_(a) of the polymer), then eachmilliequivalent of base will approximately neutralize onemilliequivalent of acid. Thus, if 0.5 milliequivalent of a strong baseper gram of polymer is added to an acidic polymer with 1.0milliequivalents of acidic moieties per gram of polymer, then the degreeof neutralization is roughly equal to 0.5.

[0045] If a relatively weak base with a pK_(a) value roughly equal tothat of the polymer's acidic moieties is used to neutralize the polymer(e.g., the base is the sodium salt of an aliphatic carboxylic acid, suchas sodium propionate, and the acidic groups on the polymer are aliphaticcarboxylic acids, such as succinate), then more base must be added toachieve the same extent of neutralization. Thus, if 1.0 milliequivalentof a base per gram of polymer, with a pK_(a) roughly equal to the pK_(a)of the polymer, is added to an acidic polymer with 1.0 milliequivalentsof acidic moieties per gram of polymer, then the degree ofneutralization is roughly also equal to 0.5.

[0046] When the degree of neutralization, a, is less than 0.9, it may beapproximated by the following equation:$\alpha = {\frac{E_{base}}{E_{polymer}} \cdot \frac{10^{{pka},{{Base} - {pka}},{Polymer}}}{1 + 10^{{pka},{{Base} - {pka}},{Polymer}}}}$

[0047] where E_(base) is the number of milliequivalents of base per gramof polymer, E_(polymer) is the number of milliequivalents of acidicmoieties (of the polymer) per gram of polymer, and pK_(a),Base andpK_(a),Polymer are the pK_(a) values of the base and polymer,respectively. It should be noted that if the calculated value of α fromthis equation is greater than 1, the degree of neutralization can beconsidered essentially 1, meaning that essentially all of the acidicmoieties on the polymer have been neutralized.

[0048] Alternatively, the degree of neutralization may be measuredexperimentally. Although not strictly applicable to organic solutions orsolid dispersions, the Henderson-Hasselbach equation can be used torelate the effective pH of an aqueous solution or a hydrated suspensionto the degree of neutralization. According to this equation theeffective pH of the solution or hydrated suspension is given as:

pH=pK_(a),Polymer−log [(1−α)/α]

[0049] As yet another alternative, the degree of neutralization may bedetermined experimentally through spectroscopic analysis or thermalmethods such as differential scanning calorimetry (DSC). Using DSC, forexample, conversion of an acidic cellulosic polymer such as HPMCAS tothe sodium or calcium salt form will lead to a measurable increase inthe glass transition temperature (“T_(g)”) of the polymer alone ordrug/polymer dispersion. The change in physical characteristic such asglass transition temperature may be used to determine the degree ofneutralization.

[0050] Typically, for an acidic polymer to be considered a “neutralizedacidic polymer,” α must be at least about 0.001 (or 0.1%), preferablyabout 0.01 (1%) and more preferably at least about 0.1 (10%). Such smalldegrees of neutralization may be acceptable because often the effectivepH of the polymer changes dramatically with small increases in thedegree of neutralization. Nonetheless, even greater degrees ofneutralization are even more preferred. Thus, α is preferably at least0.5 (meaning that at least 50% of the acidic moieties have beenneutralized) and α is more preferably at least 0.9 (meaning that atleast 90% of the acidic moieties have been neutralized).

[0051] Often the most chemically stable compositions are formed whenapproximately 100% of the acidic groups of the polymer have beenneutralized, that is, a is approximately equal to 1.0. In some casesstable dispersions are formed when excess base is present.

[0052] Yet another alternative method for determining whether asignificant fraction of the acidic moieties has been neutralized is tocompare the chemical stability of an HMG-CoA reductase inhibitor in atest composition comprising the HMG-CoA reductase inhibitor and a solidamorphous dispersion of a CETP inhibitor and a neutralized acidicpolymer with the chemical stability of the HMG-CoA reductase inhibitorin a control composition identical to the test composition except thatthe solid amorphous dispersion consists essentially of the CETPinhibitor and the acidic polymer in unneutralized form. A significantfraction of the acidic moieties of the acidic polymer have beenneutralized if the HMG-CoA reductase inhibitor degrades more slowly whenmixed with a solid amorphous dispersion comprising the neutralizedacidic polymer relative to the rate the HMG-CoA reductase inhibitordegrades when mixed with a solid amorphous dispersion comprising theacidic polymer in unneutralized form. Thus, only a portion of the acidicmoieties or acidic substituents of the polymer may need to beneutralized. Since the effective pH of an acidic polymer is raisedsignificantly by even a small degree of neutralization, a relatively lowdegree of neutralization may well result in measurable improvements inthe stability of the HMG-CoA reductase inhibitor.

[0053] Neutralized acidic polymers may be either cellulosic ornon-cellulosic as described above. A preferred class of acidic polymersconsists of cellulosic polymers with at least one ester- and/orether-linked acidic substituent in which the polymer has a degree ofsubstitution of at least 0.02 for the acidic substituent. Generally, thedegree of substitution of each substituent group can range from 0.02 to2.9 as long as the other criteria of the polymer are met. Moretypically, the degree of substitution for each substituent is from about0.1 to 2.0.

[0054] Exemplary acidic, ether-linked ionizable substituents include:carboxylic acids, such as carboxymethoxy (commonly referred to ascarboxymethyl), carboxyethoxy (commonly referred to as carboxyethyl),carboxypropoxy (commonly referred to as carboxypropyl), andcarboxyphenoxy (commonly referred to as carboxyphenyl), salicylic acid(attached to the cellulosic polymer via the phenolic hydroxyl),alkoxybenzoic acids such as ethoxybenzoic acid or propoxybenzoic acid,the various isomers of alkoxyphthalic acid such as ethoxyphthalic acidand ethoxyisophthalic acid, the various isomers of alkoxynicotinic acidsuch as ethoxynicotinic acid, and the various isomers of picolinic acidsuch as ethoxypicolinic acid, etc.; thiocarboxylic acids, such asthioacetic acid; substituted phenoxy groups, such as hydroxyphenoxy,etc.; phosphates, such as ethoxy phosphate; and sulfonates, such asethoxy sulphonate.

[0055] Exemplary ester-linked ionizable substituents include: carboxylicacids, such as succinate, citrate, phthalate, terephthalate,isophthalate, trimellitate, and the various isomers ofpyridinedicarboxylic acid, etc.; thiocarboxylic acids, such asthiosuccinate; substituted phenoxy groups, such as amino salicylic acid;phosphates, such as acetyl phosphate; and sulfonates, such as acetylsulfonate. For aromatic-substituted polymers to also have the requisiteaqueous solubility, it is also desirable that sufficient hydrophilicgroups such as hydroxypropyl or carboxylic acid functional groups beattached to the polymer to render the polymer aqueous soluble at leastat pH values where any ionizable groups are ionized. In some cases, thearomatic group may itself be ionizable, such as phthalate ortrimellitate substituents.

[0056] Exemplary acidic cellulosic polymers include such polymers ascarboxyethyl cellulose, carboxymethyl cellulose, carboxymethyl ethylcellulose, cellulose succinate, cellulose acetate succinate,hydroxyethyl cellulose succinate, hydroxyethyl cellulose acetatesuccinate, hydroxyethyl methyl cellulose succinate, hydroxyethyl methylcellulose acetate succinate, hydroxypropyl cellulose succinate,hydroxypropyl cellulose acetate succinate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methyl cellulose succinate,cellulose phthalate, cellulose acetate phthalate, methyl celluloseacetate phthalate, ethyl cellulose acetate phthalate, cellulosepropionate phthalate, hydroxyethyl methyl cellulose acetate phthalate,hydroxypropyl cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methyl cellulose acetate phthalate,hydroxypropyl cellulose acetate phthalate succinate, hydroxypropylcellulose butyrate phthalate, cellulose acetate trimellitate, methylcellulose acetate trimellitate, ethyl cellulose acetate trimellitate,hydroxypropyl cellulose acetate trimellitate, hydroxypropyl methylcellulose acetate trimellitate, hydroxypropyl cellulose acetatetrimellitate succinate, cellulose propionate trimellitate, cellulosebutyrate trimellitate, cellulose acetate terephthalate, celluloseacetate isophthalate, cellulose acetate pyridinedicarboxylate, salicylicacid cellulose acetate, hydroxypropyl salicylic acid cellulose acetate,ethylbenzoic acid cellulose acetate, hydroxypropyl ethylbenzoic acidcellulose acetate, ethyl phthalic acid cellulose acetate, ethylnicotinic acid cellulose acetate, and ethyl picolinic acid celluloseacetate.

[0057] Alternatively, the acidic polymer may be non-cellulosic.Exemplary acidic non-cellulosic polymers include carboxylicacid-functionalized vinyl polymers, such as the carboxylic acidfunctionalized polymethacrylates and carboxylic acid functionalizedpolyacrylates such as the EUDRAGITS® manufactured by Rohm Tech, Inc., ofMalden, Mass.; and carboxylic acid functionalized starches such asstarch glycolate.

[0058] The neutralized form of these acidic polymers often provideseveral advantages relative to the unneutralized form. The neutralizedform of the acidic polymer, i.e., the salt form of the polymer, tends tohave a higher glass transition temperature relative to the acidic formof the polymer. To obtain the best physical stability, particularly uponstorage for long times prior to use, it is preferred that the CETPinhibitor remain, to the extent possible, in the amorphous state. Theinventors have found that this is best achieved when the mobility of theCETP inhibitor in the concentration-enhancing polymer is relatively low.This is generally the case when the glass-transition temperature, T_(g),of the solid amorphous dispersion is substantially above the storagetemperature of the dispersion. In particular, it is preferable that theT_(g) of the solid amorphous dispersion be at least 40° C. andpreferably at least 60° C. It is preferred that theconcentration-enhancing polymer have a T_(g) of at least 40° C.,preferably at least 70° C. and more preferably greater than 100° C.(Unless otherwise specified, as used herein and in the claims, referenceto a glass transition refers to the glass transition temperaturemeasured at 50% relative humidity.) Exemplary high T_(g) polymersinclude neutralized forms of hydroxypropyl methyl cellulose acetatesuccinate, hydroxypropyl methyl cellulose phthalate, cellulose acetatephthalate, cellulose acetate trimellitate, carboxy methyl ethylcellulose, and other cellulosics that have alkylate or aromaticsubstituents or both alkylate and aromatic substituents.

[0059] Increasing the glass transition temperature of the polymer, andhence of the solid amorphous dispersion, improves the physical storagestability of the solid amorphous dispersion by decreasing the mobilityof the CETP inhibitor in the polymer matrix. Thus, solid amorphousdispersions formed from neutralized acidic polymers, which have a higherT_(g) relative to the unneutralized form, tend to be more physicallystable.

[0060] When the neutralized form of the acidic polymer comprises amultivalent cationic species such as Ca²⁺, Mg²⁺, Al³⁺, Fe²⁺, Fe³⁺, or adiamine, such as ethylene diamine, the cationic species may interactwith two or more neutralized acidic moieties on more than one polymerchain, resulting in an ionic crosslink between the polymer chains. Anacidic polymer may be considered “ionically crosslinked” if the numberof milliequivalents of multivalent cationic species per gram of polymeris at least 5%, preferably at least 10% the number of milliequivalentsof acidic moieties (of the polymer) per gram of polymer. Alternatively,an acidic polymer may be considered “ionically crosslinked” ifsufficient multivalent cationic species are present such that theneutralized acidic polymer has a higher T_(g) than the same polymercontaining essentially no multivalent cationic species. CETP inhibitormobility in dispersions formed from such ionically crosslinked polymersis particularly low relative to dispersions formed from the acidic formof the same polymers. Such ionically crosslinked polymers may be formedby neutralization of the acidic polymer using any base where thecationic counterion of the base is divalent. Thus, calcium hydroxide,calcium carbonate, magnesium acetate or ethylene diamine may be added toan acidic polymer such as cellulose acetate phthalate or hydroxypropylmethyl cellulose acetate succinate (HPMCAS) to form a neutralized,ionically crosslinked, acidic cellulosic polymer. Low CETP inhibitormobility in such polymers may be indicated by high T_(g) values or, moretypically, a decrease in the magnitude of the heat capacity increase inthe vicinity of the T_(g) or, in some cases, the absence of any apparentT_(g) when the solid amorphous dispersion is subjected to differentialthermal analysis. Thus, when sufficient calcium hydroxide is added to anacidic polymer, e.g., HPMCAS, such that the degree of neutralization isnear 1, no T_(g) is apparent when the neutralized polymer is subjectedto differential thermal analysis.

[0061] The neutralized form of the acidic polymer tends to be lessreactive than the acidic polymer. Thus, in addition to minimizingreactions of the HMG-CoA reductase inhibitor with the polymer, theselection of a neutralized acidic enteric polymer may also minimizereactions of the polymer with other excipients.

[0062] Neutralized acidic polymers may be formed by any conventionalmethod known in the art which results in the desired degree ofneutralization. In general, the acidic polymer is neutralized throughthe addition of a sufficient amount of base to a solution or compositioncontaining the acidic polymer. The polymer may be neutralized prior toformation of the solid amorphous dispersion. For example, a base may beadded to a solution of the acidic polymer resulting in neutralization ofthe polymer's acidic functional groups. Alternatively, the acidicpolymer may be neutralized during formation of the solid amorphousdispersion, or may be neutralized following formation of the solidamorphous dispersion.

[0063] A wide range of bases may be used to neutralize the acidicpolymer. The term “base” is used broadly to include not only strongbases such as sodium hydroxide, but also weak bases and buffers that arecapable of achieving the desired degree of neutralization. Examples ofbases include hydroxides, such as sodium hydroxide, calcium hydroxide,ammonium hydroxide, and choline hydroxide; bicarbonates, such as sodiumbicarbonate, potassium bicarbonate, and ammonium bicarbonate;carbonates, such as ammonium carbonate, calcium carbonate, and sodiumcarbonate; amines, such as tris(hydroxymethyl)amino methane,ethanolamine, diethanolamine, N-methyl glucamine, glucosamine,ethylenediamine, N,N′-dibenzylethylenediamine,N-benzyl-2-phenethylamine, cyclohexylamine, cyclopentylamine,diethylamine, isopropylamine, diisopropylamine, dodecylamine, andtriethylamine; proteins, such as gelatin; amino acids such as lysine,arginine, guanine, glycine, and adenine; polymeric amines, such aspolyamino methacrylates, such as Eudragit E; conjugate bases of variousacids, such as sodium acetate, sodium benzoate, ammonium acetate,disodium phosphate, trisodium phosphate, calcium hydrogen phosphate,sodium phenolate, sodium sulfate, ammonium chloride, and ammoniumsulfate; salts of EDTA, such as tetra sodium EDTA; and salts of variousacidic polymers such as sodium starch glycolate, sodium carboxymethylcellulose and sodium polyacrylic acid. The use of the bicarbonates is insome cases preferred, as these generate carbon dioxide during theneutralization process, which can be removed easily followingneutralization.

[0064] As described previously, dispersions that contain significantquantities of a divalent cationic or multivalent cationic species suchas Ca²⁺, Mg²⁺, or a diamine such as ethylene diamine are particularlydesirable as they may ionically crosslink the concentration-enhancingpolymer. This may conveniently be accomplished by adding such species intheir basic form. Thus, exemplary bases containing a dicationic speciesinclude: calcium hydroxide, calcium acetate, calcium carbonate,magnesium hydroxide, magnesium stearate, aluminum hydroxide, ethylenediamine, polyamino methyacrylate, or any other pharmaceuticallyacceptable compound that may form a dicationic or polycationic speciesin the solid amorphous dispersion.

[0065] In one neutralization method, the polymer is neutralized prior toformation of the solid amorphous dispersion. The acidic polymer is firstdissolved in a suitable solvent prior to addition of the base. Suitablesolvents include water; ketones, such as acetone; alcohols, such asmethanol, ethanol, isopropanol; and other solvents such astetrahydrofuran, benzene, and dichloromethane. Mixtures of solvents,including mixtures of water and one or more organic solvents, may alsobe used. In particular, when organic solvents are used, addition of atleast a small amount of water is often preferred to facilitate theneutralization process and to minimize excessively high or low pHvalues. The solvent may be selected such that it is a solvent for theneutralized acidic polymer but not necessarily a solvent for the acidicpolymer prior to neutralization. This may facilitate isolation of theneutralized acidic polymer. Thus, prior to adding the base, the acidicpolymer is not completely dissolved in the solvent. As the base isadded, the neutralized acidic polymer dissolves.

[0066] For example, the acidic polymer HPMCAS may be neutralized byaddition of a base to an aqueous solution containing HPMCAS. HPMCAS hasa pK_(a) of about 5. One procedure for neutralizing HPMCAS is to suspendthe HPMCAS in distilled water. A base, such as sodium bicarbonate canthen be added to this solution. As the base is added, the succinategroups on HPMCAS are neutralized, forming the sodium salt form of HPMCASand at the same time the pH of the solution increases. When the pH ofthe solution reaches about 5, the pK_(a) of the acidic moieties(succinate groups) of the polymer, the degree of neutralization, α, is0.5. More base may be added, increasing the pH of the solution andincreasing the extent of neutralization. Care must be taken, however,not to increase the pH too high, as at high pH (greater than about 8),the excess base can lead to degradation of the polymer. In the case ofHPMCAS, such degradation can take the form of hydrolysis of ester-linkedgroups such as acetate or succinate or even cleavage of the cellulosicbackbone of the polymer.

[0067] Following neutralization, the neutralized acidic polymer may beisolated and purified using methods known in the art. Examples ofsuitable methods include precipitation using a non-solvent, evaporation,rotoevaporation, spray-drying, and lyophilization. The neutralizedacidic polymer can then be used to form the solid amorphous dispersionwith the CETP inhibitor using the methods described below.

[0068] In another method, the neutralized acidic polymer is not isolatedfrom the solvent, but instead, the CETP inhibitor is added to thepolymer/solvent solution and the solid amorphous dispersion formeddirectly from this mixture. Examples of processes for forming the solidamorphous dispersion from such a solution are described below inconnection with the discussion regarding formation of dispersions.

[0069] Another method for neutralizing an acidic concentration-enhancingpolymer is to neutralize the polymer after the solid amorphousdispersion has been formed. In this method, a base is blended with thesolid amorphous dispersion of CETP inhibitor and acidic polymer.Exemplary bases that may be used to neutralize the acidic polymerinclude any of those listed above for neutralization of a polymer insolution but include, in particular, salts of acidic polymers such assodium starch glycolate, cross carmellose sodium, and sodiumcarboxymethyl cellulose; amine functionalized polymers such asaminomethacryrates, amino acrylates, chitin, and proteins; inorganicbases such as tribasic calcium phosphate, calcium carbonate, disodiumhydrogen phosphate and aluminum hydroxide; salts of acidic compoundssuch as magnesium stearate, sodium acetate, and potassium lactate; andamines such as meglumine and mono-, di- and tri-ethanolamine. Many ofthese bases, such as phosphate, carbonate and carboxylate salts, may beadded in excess and as such may act as buffers, maintaining a relativelyneutral pH (e.g., pH between about 5 and 9) in the solid amorphousdispersion. The amount of base to be blended with the solid amorphousdispersion should generally be in the range from about 0.1 to about 2.0equivalents of base per equivalent of the acidic polymer moieties. Insome cases, it may be necessary to add water, such as by wet granulationor by storing at elevated humidity, to speed the neutralization process.

[0070] The amount of base to be blended with the solid amorphousdispersion may be determined by various techniques. For example, thepolymer and CETP inhibitor may be dissolved or slurried in water and thepH monitored as base is added. The amount of base per amount of CETPinhibitor and polymer to achieve the desired pH may be noted. Generally,adding sufficient base to substantially increase the pH may besufficient. The amount of base required to raise the pH to a value near6 to 8 is often preferred.

[0071] The base and solid amorphous dispersion may be blended togetherto create a physical mixture using any conventional method known in theart. Thus, the base and solid amorphous dispersion may be blendedtogether using wet- or dry-granulation. A high degree of blending ormixing is generally preferred in order to achieve maximum neutralizationof the acidic polymer using this method. In general, the neutralizationis facilitated by the presence of solvent, particularly water. Forexample, simple storage of the blended composition as a bulk material orin the form of a dosage form such as a tablet, granule or capsule underhumid conditions for a period of a few hours to 30 days can result insufficient neutralization of the acidic polymer dispersion. Likewise,the neutralization process may be facilitated by wet granulationprocesses in which the blend is relatively wet during at least a portionof the processing time.

[0072] In one embodiment, the solid amorphous dispersion of CETPinhibitor and acidic polymer is blended with calcium carbonate topartially neutralize the acidic polymer. Preferably, the weight ratio ofcalcium carbonate to acidic polymer is at least 0.10, more preferably atleast 0.15, and most preferably at least 0.20.

[0073] Neutralization may be quantified by numerous methods, includingstorage and measurement of reduced drug degradation rates, spectroscopicanalysis, potentiometric analysis, and thermal methods such asdifferential scanning calorimetry (DSC). Using DSC, for example,conversion of an acidic cellulosic polymer such as HPMCAS to the sodiumor calcium salt form will lead to a measurable increase in the glasstransition temperature of the polymer alone or the solid amorphousdispersion. In the case of adding calcium the glass transition may becompletely absent from the DSC data.

[0074] In addition, when solid dispersions are made by thermal processessuch as a melt-congeal process, or an extrusion process, using, forexample, a twin-screw extruder, that may form a solid amorphousdispersion by a combination of thermal and mechanical means, then thebasic excipient may be blended with the CETP inhibitor and acidicpolymer and the blend then fed to the melt-congeal or extrusion processapparatus. Such processes may also optionally include small amounts ofsolvent. Neutralization may occur completely or in part duringprocessing as the heat, mechanical shear and solvent, if present,facilitate the neutralization process.

CHEMICAL STABILITY

[0075] Dosage forms in which the concentration-enhancing polymer used toform the solid amorphous dispersion is neutral or neutralized exhibitacceptably low rates of degradation of the HMG-CoA reductase inhibitorin the dosage form. The compositions and dosage forms of the presentinvention provide improved chemical stability of the HMG-CoA reductaseinhibitor relative to a control composition. Where the compositioncomprises a solid amorphous dispersion of a CETP inhibitor and aneutralized acidic concentration-enhancing polymer and an HMG-CoAreductase inhibitor, the control composition is essentially the same asthe composition except that the solid amorphous dispersion contains theun-neutralized acidic concentration-enhancing polymer. Where thecomposition comprises a solid amorphous dispersion of a CETP inhibitorand a neutral concentration-enhancing polymer and an HMG-CoA reductaseinhibitor, the control composition is essentially the same as thecomposition except that the solid amorphous dispersion contains theacidic concentration-enhancing polymer HPMCAS instead of the neutralpolymer. The HPMCAS used in the control composition should have aminimum degree of substitution of succinate groups (O(CO)CH₂CH₂(CO)OH)of at least 4 wt % (or at least about 100 milliequivalents of carboxylicacid functional groups per mole of polymer). A suitable grade of HPMCASto use in the control composition is the “H” grade, available from ShinEtsu (Tokyo, Japan).

[0076] In general, degradation of the HMG-CoA reductase inhibitor may bemeasured using any conventional method for measuring the potency orpurity of drug in a pharmaceutical composition. For example, the amountof active HMG-CoA reductase inhibitor present in a composition may beinitially measured using high-performance liquid chromatography (HPLC)or other analytical techniques well known in the art. Alternatively, theamount of HMG-CoA reductase inhibitor initially present may becalculated from the amount of drug present in the composition. Thepotency of the composition is then measured after storage at controlledtemperature and humidity conditions for an appropriate period of time. Adecrease in potency indicates that a chemical reaction has occurred,leading to a decrease in the amount of active drug present in thecomposition, and is an indication of poor chemical stability.

[0077] An alternative method used to evaluate chemical stability is toanalyze the rate of increase in the amount of drug degradant(s) in thecomposition, which would indicate reaction of the HMG-CoA reductaseinhibitor. An HPLC or other analytical technique may be used todetermine the concentration of drug degradant(s) in a composition. Theamount of the degradant(s) is measured before and after storage undercontrolled storage conditions. The amount of increase in the drugdegradant(s) may be used to determine the amount of decrease in “percentdrug purity,” defined as 100 times the total amount of drug presentdivided by the amount of drug initially$\text{percent drug purity} = {100 \times \left( \frac{\text{total drug present}}{\text{drig initially present}} \right)}$

[0078] When the drug purity is calculated from the total amount ofimpurities, percent drug purity may be calculated by assuming that thedrug initially present, given in wt %, is equal to 100 wt % minus the wt% of total initial impurities, and that total drug present is equal to100 wt % minus the wt % of total impurities after storage, that is, atsome later time. This method of calculating percent drug purity is bythe formula:$\text{percent drug purity} = {100 \times \left\lbrack {1 - \left( \frac{\text{total impurities}}{\text{drug initially present}} \right)} \right\rbrack}$

[0079] The rate at which drug degradation occurs is generally dependenton the storage conditions. The HMG-CoA reductase inhibitor, whenformulated in a composition of the present invention, should be stableat ambient temperature and humidity conditions (e.g., 20% to 60%relative humidity (RH)) for long periods of time, such as months oryears. However, to expedite testing, the storage conditions may employelevated temperature and/or humidity to simulate longer storage times atambient conditions. The storage time may vary from a few days to weeksor months, depending on the reactivity of the drug and the storageconditions.

[0080] A “degree of degradation” of drug following storage may bedetermined by subtracting the final percent drug purity (determinedeither by measuring the decrease in drug present or the increase in drugimpurities present) from the initial percent drug purity. For example, asample of composition initially containing 100 mg HMG-CoA reductaseinhibitor and having no measurable impurities would have an initialpercent drug purity of 100 wt %. If, after storage, the amount ofHMG-CoA reductase inhibitor in the sample decreases to 95 mg, the finalpercent drug purity would be 95 wt % and the degree of degradation wouldbe 100 wt % less 95 wt %, or 5 wt %. Alternatively, if 100 mg of HMG-CoAreductase inhibitor were found to initially have 1 mg of impuritiespresent, it would have an initial percent drug purity of 99 wt %. If,after storage, the total impurities present had increased to 6 wt %, thefinal percent drug purity would be 94 wt % and the degree of degradationwould be 99 wt % less 94 wt %, or 5 wt %.

[0081] Alternatively, degree of degradation can be determined bysubtracting the amount of one or more specific drug degradants initiallypresent from the amount of that specific degradant present afterstorage. Such a measure is useful where there are several drugdegradants, of which only one or a few is of concern. For example, if anHMG-CoA reductase inhibitor initially contained a specific degradant ata concentration of 1 wt % and after storage the concentration of thatdegradant was 6 wt %, the degree of degradation would be 6 wt % less 1wt %, or 5 wt %.

[0082] A relative degree of improvement in chemical stability of theHMG-CoA reductase inhibitor in a test composition may be determined bytaking the ratio of the degree of degradation of the HMG-CoA reductaseinhibitor in a control composition and the degree of degradation of theHMG-CoA reductase inhibitor in a test composition under the same storageconditions for the same storage time period. The test composition issimply the composition of the solid amorphous dispersion of the CETPinhibitor and neutral or neutralized concentration-enhancing polymer,the HMG-CoA reductase inhibitor, and optional additional excipients.Where the concentration-enhancing polymer is a neutral polymer, thecontrol composition is the same as the test composition, except that theconcentration-enhancing polymer is the acidic concentration-enhancingpolymer HPMCAS, as previously described. Where theconcentration-enhancing polymer is a neutralized acidic polymer, thecontrol composition is the same as the test composition, except that thepolymer is the unneutralized form of the acidic polymer. For example,where the degree of degradation of the HMG-CoA reductase inhibitor in atest composition is 1 wt %, and the degree of degradation of the HMG-CoAreductase inhibitor in a control composition is 5 wt %, the relativedegree of improvement is 5 wt %/1 wt % equals 5.0. For compositions anddosage forms in which the solid amorphous dispersion comprises a neutralor neutralized acidic polymer, the relative degree of improvement is atleast 1.1. Preferably, the relative degree of improvement is at least1.25, more preferably at least 2.0, and even more preferably at least3.0, most preferably at least 5.0. In fact, some compositions of thepresent invention may achieve a relative degree of improvement greaterthan 20.

[0083] The particular storage conditions and time of storage may bechosen as convenient depending on the degree of acid-sensitivity of theHMG-CoA reductase inhibitor, the particular concentration-enhancingpolymer used in the solid amorphous dispersion, and the ratio of HMG-CoAreductase inhibitor to polymer in the composition. Where the HMG-CoAreductase inhibitor is particularly acid-sensitive, or where thecomposition has a low ratio of HMG-CoA reductase inhibitor to polymer,then shorter storage time periods may be used. Where the rate ofdegradation is linear, the relative degree of improvement will beindependent of the storage time. However, where the rate of degradationis non-linear under controlled storage conditions, the stability testused to compare the test composition with the control composition ispreferably chosen such that the degree of degradation is sufficientlylarge that it may be accurately measured. Typically, the time period ischosen so as to observe a degree of degradation in the controlcomposition of at least 0.1 wt % to 0.2 wt %. However, the time periodis not so long that the ratio of HMG-CoA reductase inhibitor to polymerchanges substantially. Typically, the time period is such that theobserved degree of degradation for the test composition is less than 50wt % and preferably less than 20 wt %. When rate of degradation in thecontrol composition is relatively slow, the test is preferably conductedover a long enough period of time under controlled storage conditions toallow a meaningful comparison of the stability of the test compositionwith the control composition.

[0084] A stability test which may be used to test whether a compositionor dosage form meets the chemical stability criteria described above isstorage of the test dispersion and the control dispersion for six monthsat 40° C. and 75% relative humidity (RH) or for three months at 50° C.and 75% RH. A relative degree of improvement may become apparent withina shorter time, such as three to five days, and shorter storage timesmay be used for some very acid-sensitive HMG-CoA reductase inhibitors.When comparing dispersions under storage conditions that approximateambient conditions, e.g., 30° C. and 60% RH, the storage period may needto be several months up to two years.

[0085] In addition, it is preferred that the compositions comprising anHMG-CoA reductase inhibitor and a solid amorphous dispersion result indrug stability such that the HMG-CoA reductase inhibitor has a degree ofdegradation of less than about 5 wt %, more preferably less than about 2wt %, even more preferably less than about 0.5 wt %, and most preferablyless than about 0.1 wt % when stored at 40° C. and 75% RH for sixmonths, or less than about 5 wt %, more preferably less than about 2 wt%, even more preferably less than about 0.5 wt %, and more preferablyless than about 0.1 wt %, when stored at 30° C. and 60% RH for one year.Nevertheless, the compositions of the present invention may have adegree of degradation that is much greater than the preferred values, solong as the composition achieves the degree of improvement relative to acontrol composition as described above.

CHOLESTERYL ESTER TRANSFER PROTEIN INHIBITORS

[0086] The CETP inhibitor may be any compound capable of inhibiting thecholesteryl ester transfer protein. Solid amorphous dispersions areparticularly useful for CETP inhibitors that have sufficiently lowaqueous solubility, low bioavailability or slow rate of absorption suchthat it is desirable to increase their concentration in an aqueousenvironment of use. The CETP inhibitor is typically “sparinglywater-soluble,” which means that the CETP inhibitor has a minimumaqueous solubility of less than about 1 to 2 mg/mL at anyphysiologically relevant pH (e.g., pH 1-8) and at about 22° C. Many CETPinhibitors are “substantially water-insoluble,” which means that theCETP inhibitor has a minimum aqueous solubility of less than about 0.01mg/mL (or 10 μg/ml) at any physiologically relevant pH (e.g., pH 1-8)and at about 22° C. (Unless otherwise specified, reference to aqueoussolubility herein and in the claims is determined at about 22° C.)Compositions of the present invention find greater utility as thesolubility of the CETP inhibitors decreases, and thus are preferred forCETP inhibitors with solubilities less than about 10 μg/mL, and evenmore preferred for CETP inhibitors with solubilities less than about 1μg/mL. Many CETP inhibitors have even lower solubilities (some even lessthan 0.1 μg/mL), and require dramatic concentration enhancement to besufficiently bioavailable upon oral dosing for effective plasmaconcentrations to be reached at practical doses.

[0087] In general, the CETP inhibitor has a dose-to-aqueous solubilityratio greater than about 100 mL, where the solubility (mg/mL) is theminimum value observed in any physiologically relevant aqueous solution(e.g., those with pH values from 1 to 8) including USP simulated gastricand intestinal buffers, and dose is in mg. Compositions of the presentinvention, as mentioned above, find greater utility as the solubility ofthe CETP inhibitor decreases and the dose increases. Thus, thecompositions are preferred as the dose-to-solubility ratio increases,and thus are preferred for dose-to-solubility ratios greater than 1000mL, and more preferred for dose-to-solubility ratios greater than about5000 ml. The dose-to-solubility ratio may be determined by dividing thedose (in mg) by the aqueous solubility (in mg/ml).

[0088] Oral delivery of many CETP inhibitors is particularly difficultbecause their aqueous solubility is usually extremely low, typicallybeing less than 2 μg/ml, often being less than 0.1 μg/ml. Such lowsolubilities are a direct consequence of the particular structuralcharacteristics of species that bind to CETP and thus act as CETPinhibitors. This low solubility is primarily due to the hydrophobicnature of CETP inhibitors. Log P, defined as the base 10 logarithm ofthe ratio of the drug solubility in octanol to the drug solubility inwater, is a widely accepted measure of hydrophobicity. Log P may bemeasured experimentally or calculated using methods known in the art.Calculated Log P values are often referred to by the calculation method,such as Alog P, Clog P, and Mlog P. In general, Log P values for CETPinhibitors are greater than 4 and are often greater than 5. Thus, thehydrophobic and insoluble nature of CETP inhibitors as a class pose aparticular challenge for oral delivery. Achieving therapeutic druglevels in the blood by oral dosing of practical quantities of druggenerally requires a large enhancement in drug concentrations in thegastrointestinal fluid and a resulting large enhancement inbioavailability. Such enhancements in drug concentration ingastrointestinal fluid typically need to be at least about 10-fold andoften at least about 50-fold or even at least about 200-fold to achievedesired blood levels. Surprisingly, the solid amorphous dispersions ofthe present invention have proven to have the required largeenhancements in drug concentration and bioavailability.

[0089] In contrast to conventional wisdom, the relative degree ofenhancement in aqueous concentration and bioavailability provided by thesolid amorphous dispersions generally improves for CETP inhibitors assolubility decreases and hydrophobicity increases. In fact, theinventors have recognized a subclass of these CETP inhibitors that areessentially aqueous insoluble, highly hydrophobic, and are characterizedby a set of physical properties. This subclass exhibits dramaticenhancements in aqueous concentration and bioavailability whenformulated using a solid amorphous dispersion.

[0090] The first property of this subclass of essentially insoluble,hydrophobic CETP inhibitors is extremely low aqueous solubility. Byextremely low aqueous solubility is meant that the minimum aqueoussolubility at physiologically relevant pH (pH of 1 to 8) is less thanabout 10 μg/ml and preferably less than about 1 μg/ml.

[0091] A second property is a very high dose-to-solubility ratio.Extremely low solubility often leads to poor or slow absorption of thedrug from the fluid of the gastrointestinal tract, when the drug isdosed orally in a conventional manner. For extremely low solubilitydrugs, poor absorption generally becomes progressively more difficult asthe dose (mass of drug given orally) increases. Thus, a second propertyof this subclass of essentially insoluble, hydrophobic CETP inhibitorsis a very high dose (in mg) to solubility (in mg/ml) ratio (ml). By“very high dose-to-solubility ratio” is meant that thedose-to-solubility ratio has a value of at least 1000 ml, and preferablyat least 5,000 ml, and more preferably at least 10,000 ml.

[0092] A third property of this subclass of essentially insoluble,hydrophobic CETP inhibitors is that they are extremely hydrophobic. Byextremely hydrophobic is meant that the Log P value of the drug, has avalue of at least 4.0, preferably a value of at least 5.0, and morepreferably a value of at least 5.5.

[0093] A fourth property of this subclass of essentially insoluble CETPinhibitors is that they have a low melting point. Generally, drugs ofthis subclass will have a melting point of about 150° C. or less, andpreferably about 140° C. or less.

[0094] Primarily, as a consequence of some or all of these fourproperties, CETP inhibitors of this subclass typically have very lowabsolute bioavailabilities. Specifically, the absolute bioavailabilityof drugs in this subclass when dosed orally in their undispersed stateis less than about 10% and more often less than about 5%.

[0095] For this subclass of CETP inhibitors, the CETP inhibitor, whendispersed in the solid amorphous dispersion, should be at leastsubstantially amorphous, and more preferably is almost completelyamorphous, as described below. In addition, the solid amorphousdispersion should be substantially homogeneous. As discussed below, suchdispersions may be made by mechanical processes, such as milling andextrusion; melt processes, such as fusion, melt-extrusion, andmelt-congealing; and solvent processes, such as non-solventprecipitation, spray coating, and spray-drying. When prepared in thisfashion, this class of essentially insoluble, hydrophobic CETPinhibitors often exhibits dramatic enhancements in aqueous concentrationin the use environment and in bioavailability when dosed orally. Whilethe degree of enhancement will depend on the particularconcentration-enhancing polymer, when preferred concentration-enhancingpolymers are used (as discussed below), such compositions may provide amaximum drug concentration (MDC) in an aqueous use environment that isat least about 50-fold, and preferably at least about 200-fold, theequilibrium concentration of a control composition comprising anequivalent quantity of the essentially insoluble, hydrophobic CETPinhibitor but free from the concentration-enhancing polymer. Likewise,the compositions also display in an aqueous use environment an areaunder the concentration versus time curve (AUC), for any period of atleast 90 minutes between the time of introduction into the useenvironment and about 270 minutes following introduction into the useenvironment that is at least about 25-fold, and preferably at leastabout 100-fold, that of the control composition comprising an equivalentquantity of drug but free from the concentration-enhancing polymer.

[0096] In the following, by “pharmaceutically acceptable forms” thereofis meant any pharmaceutically acceptable derivative or variation,including stereoisomers, stereoisomer mixtures, enantiomers, solvates,hydrates, isomorphs, polymorphs, salt forms and prodrugs.

[0097] One class of CETP inhibitors that finds utility with the presentinvention consists of oxy substituted4-carboxyamino-2-methyl-1,2,3,4-tetrahydroquinolines having the FormulaI

[0098] and pharmaceutically acceptable forms thereof;

[0099] wherein R_(I-1) is hydrogen, Y_(I), W_(I)-X_(I), W_(I)-Y_(I);

[0100] wherein W_(I) is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;

[0101] X_(I) is —O—Y_(I), —S—Y_(I), —N(H)—Y_(I), or —N—(Y_(I))₂;

[0102] wherein Y, for each occurrence is independently Z_(I) or a fullysaturated, partially unsaturated or fully unsaturated one to tenmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with one or twoheteroatoms selected independently from oxygen, sulfur and nitrogen andsaid carbon is optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with hydroxy, saidcarbon is optionally mono-substituted with oxo, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono-, or di-substituted with oxo, and said carbon chain is optionallymono-substituted with Z_(I);

[0103] wherein Z_(I) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, or,a bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

[0104] wherein said Z_(I) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxyl, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxyl,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines;

[0105] R_(I-3) is hydrogen or Q_(I);

[0106] wherein Q_(I) is a fully saturated, partially unsaturated orfully unsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono-, or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(I);

[0107] wherein V_(I) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

[0108] wherein said V_(I) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carbamoyl, mono-N- or di-N,N-(C₁-C₆) alkylcarbamoyl, carboxyl,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl or (C₂-C₆)alkenyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxyl,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl or (C₂-C₆)alkenyl substituents are also optionallysubstituted with from one to nine fluorines;

[0109] R_(I-4) is Q_(I-1) or V_(I-1)

[0110] wherein Q_(I-1) is a fully saturated, partially unsaturated orfully unsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono-, or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(I-1);

[0111] wherein V_(I-1) is a partially saturated, fully saturated orfully unsaturated three to six membered ring optionally having one totwo heteroatoms selected independently from oxygen, sulfur and nitrogen;

[0112] wherein said V_(I-1) substituent is optionally mono-, di-, tri-,or tetra-substituted independently with halo, (C₁ -C₆)alkyl,(C₁-C₆)alkoxy, amino, nitro, cyano, (C₁-C₆)alkyloxycarbonyl, mono-N- ordi-N,N-(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituent isoptionally mono-substituted with oxo, said (C₁-C₆)alkyl substituent isalso optionally substituted with from one to nine fluorines;

[0113] wherein either R_(I-3) must contain V_(I) I or R₁₋₄ must containV_(I-1); and R_(I-5), R_(I-6), R_(I-7) and R_(I-8) are eachindependently hydrogen, hydroxy or oxy wherein said oxy is substitutedwith T_(I) or a partially saturated, fully saturated or fullyunsaturated one to twelve membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one or two heteroatoms selected independently from oxygen,sulfur and nitrogen and said carbon is optionally mono-, di- ortri-substituted independently with halo, said carbon is optionallymono-substituted with hydroxy, said carbon is optionallymono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono- ordi-substituted with oxo, and said carbon chain is optionallymono-substituted with T_(I);

[0114] wherein T_(I) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

[0115] wherein said T_(I) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines.

[0116] Compounds of Formula I are disclosed in commonly assigned U.S.Pat. No. 6,140,342, the complete disclosure of which is hereinincorporated by reference.

[0117] In a preferred embodiment, the CETP inhibitor is selected fromone of the following compounds of Formula I:

[0118] [2R,4S]4-[(3,5-dichloro-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0119] [2R,4S]4-[(3,5-dinitro-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0120] [2R,4S]4-[(2,6-dichloro-pyridin-4-ylmethyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0121] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0122] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0123] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester,

[0124] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0125] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-ethoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0126] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid 2,2,2-trifluoro-ethyl ester;

[0127] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid propyl ester;

[0128] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester;

[0129] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-6-trifluoromethoxy-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester,

[0130] [2R,4S](3,5-bis-trifluoromethyl-benzyl)-(1-butyryl-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamicacid methyl ester;

[0131] [2R,4S](3,5-bis-trifluoromethyl-benzyl)-(1-butyl-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamicacid methyl ester;

[0132] [2R,4S](3,5-bis-trifluoromethyl-benzyl)-[1-(2-ethyl-butyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-carbamicacid methyl ester, hydrochloride

[0133] Another class of CETP inhibitors that finds utility with thepresent invention consists of4-carboxyamino-2-methyl-1,2,3,4,-tetrahydroquinolines, having theFormula II

[0134] and pharmaceutically acceptable forms thereof;

[0135] wherein R_(II-1) is hydrogen, Y_(II), W_(II)-X_(II),W_(II)-Y_(II);

[0136] wherein W_(II) is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;

[0137] X_(II) is —O—Y_(II), —S—Y_(II), —N(H)—Y_(II) or —N—(Y_(II))₂;

[0138] wherein Y_(II) for each occurrence is independently Z_(II) or afully saturated, partially unsaturated or fully unsaturated one to tenmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with one or twoheteroatoms selected independently from oxygen, sulfur and nitrogen andsaid carbon is optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with hydroxy, saidcarbon is optionally mono-substituted with oxo, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono-, or di-substituted with oxo, and said carbon chain is optionallymono-substituted with Z_(II);

[0139] Z_(II) is a partially saturated, fully saturated or fullyunsaturated three to twelve membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

[0140] wherein said Z_(II) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl is also optionally substituted with from one to ninefluorines;

[0141] R_(II-3) is hydrogen or Q_(II);

[0142] wherein Q_(II) is a fully saturated, partially unsaturated orfully unsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(II);

[0143] wherein V_(II) is a partially saturated, fully saturated or fullyunsaturated three to twelve membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, or,a bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

[0144] wherein said V_(II), substituent is optionally mono-, di-, tri-,or tetra-substituted independently with halo, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro,cyano, oxo, carboxamoyl, mono-N- or di-N,N-(C₁-C₆) alkylcarboxamoyl,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl or (C₂-C₆)alkenyl substituent is optionallymono-, di- or tri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino or said(C₁-C₆)alkyl or (C₂-C₆)alkenyl substituents are optionally substitutedwith from one to nine fluorines;

[0145] R_(II-4) is Q_(II-1) or V_(II-1)

[0146] wherein Q_(II-1) a fully saturated, partially unsaturated orfully unsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(II-1);

[0147] wherein V_(II-1) is a partially saturated, fully saturated orfully unsaturated three to six membered ring optionally having one totwo heteroatoms selected independently from oxygen, sulfur and nitrogen;

[0148] wherein said V_(II-1) substituent is optionally mono-, di-, tri-,or tetra-substituted independently with halo, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, amino, nitro, cyano, (C₁-C₆)alkyloxycarbonyl, mono-N- ordi-N,N-(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituent isoptionally mono-substituted with oxo, said (C₁-C₆)alkyl substituent isoptionally substituted with from one to nine fluorines;

[0149] wherein either R_(II-3) must contain V_(II) or R_(II-4) mustcontain V_(II-1); and

[0150] R_(II-5), R_(II-6), R_(II-7) and R_(II-8) are each independentlyhydrogen, a bond, nitro or halo wherein said bond is substituted withT_(II) or a partially saturated, fully saturated or fully unsaturated(C₁-C₁₂) straight or branched carbon chain wherein carbon may optionallybe replaced with one or two heteroatoms selected independently fromoxygen, sulfur and nitrogen wherein said carbon atoms are optionallymono-, di- or tri-substituted independently with halo, said carbon isoptionally mono-substituted with hydroxy, said carbon is optionallymono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono- ordi-substituted with oxo, and said carbon is optionally mono-substitutedwith T_(II);

[0151] wherein T_(II) is a partially saturated, fully saturated or fullyunsaturated three to twelve membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, or,a bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

[0152] wherein said T_(II) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines; provided that at least one of substituents R_(II-5),R_(II-6), R_(II-7) and R_(II-8) is not hydrogen and is not linked to thequinoline moiety through oxy.

[0153] Compounds of Formula II are disclosed in commonly assigned U.S.Pat. No. 6,147,090, the complete disclosure of which-is hereinincorporated by reference.

[0154] In a preferred embodiment, the CETP inhibitor is selected fromone of the following compounds of Formula II:

[0155] [2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-7-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0156] [2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-chloro-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0157] [2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-chloro-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0158] [2R,4S] 4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2,6,7-trimethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester

[0159] [2R,4S)4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-diethyl-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0160] [2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-ethyl-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0161] [2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester.

[0162] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

[0163] Another class of CETP inhibitors that finds utility with thepresent invention consists of annulated4-carboxyamino-2-methyl-1,2,3,4,-tetrahydroquinolines, having theFormula III

[0164] and pharmaceutically acceptable forms thereof;

[0165] wherein R_(III-1) is hydrogen, Y_(III), W_(III)-X_(III),W_(III)-Y_(III);

[0166] wherein W_(III) is a carbonyl, thiocarbonyl, sulfinyl orsulfonyl;

[0167] X_(III) is —O—Y_(III), —S—Y_(III), —N(H)—Y_(III) or—N—(Y_(III))₂;

[0168] Y_(III) for each occurrence is independently Z_(III) or a fullysaturated, partially unsaturated or fully unsaturated one to tenmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with one or twoheteroatoms selected independently from oxygen, sulfur and nitrogen andsaid carbon is optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with hydroxy, saidcarbon is optionally mono-substituted with oxo, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono-, or di-substituted with oxo, and said carbon chain is optionallymono-substituted with Z_(III);

[0169] wherein Z_(III) is a partially saturated, fully saturated orfully unsaturated three to twelve membered ring optionally having one tofour heteroatoms selected independently from oxygen, sulfur andnitrogen, or a bicyclic ring consisting of two fused partiallysaturated, fully saturated or fully unsaturated three to six memberedrings, taken independently, optionally having one to four heteroatomsselected independently from nitrogen, sulfur and oxygen;

[0170] wherein said Z_(III) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl optionally substituted with from one to nine fluorines;

[0171] R_(III-3) is hydrogen or Q_(III);

[0172] wherein Q_(III) is a fully saturated, partially unsaturated orfully unsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(III);

[0173] wherein V_(III) is a partially saturated, fully saturated orfully unsaturated three to twelve membered ring optionally having one tofour heteroatoms selected independently from oxygen, sulfur andnitrogen, or a bicyclic ring consisting of two fused partiallysaturated, fully saturated or fully unsaturated three to six memberedrings, taken independently, optionally having one to four heteroatomsselected independently from nitrogen, sulfur and oxygen;

[0174] wherein said V_(III) substituent is optionally mono-, di-, tri-,or tetra-substituted independently with halo, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro,cyano, oxo, carboxamoyl, mono-N- or di-N,N-(C₁-C₆) alkylcarboxamoyl,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl or (C₂-C₆)alkenyl substituent is optionallymono-, di- or tri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino or said(C₁-C₆)alkyl or (C₂-C₆)alkenyl are optionally substituted with from oneto nine fluorines;

[0175] R_(III-4) is Q_(III) or V_(III-1);

[0176] wherein Q_(III-1) a fully saturated, partially unsaturated orfully unsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(III-1);

[0177] wherein V_(III-1) is a partially saturated, fully saturated orfully unsaturated three to six membered ring optionally having one totwo heteroatoms selected independently from oxygen, sulfur and nitrogen;

[0178] wherein said V_(III-1) substituent is optionally mono-, di-,tri-, or tetra-substituted independently with halo, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, amino, nitro, cyano, (C₁-C₆)alkyloxycarbonyl, mono-N- ordi-N,N-(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituent isoptionally mono-substituted with oxo, said (C₁-C₆)alkyl substituentoptionally having from one to nine fluorines;

[0179] wherein either R_(III-3) must contain V_(III) or R_(III -4) mustcontain V_(III-1); and R_(III-5) and R_(III-6), or R_(III-6) andR_(III-7), and/or R_(III-7) and R_(III-8) are taken together and form atleast one four to eight membered ring that is partially saturated orfully unsaturated optionally having one to three heteroatomsindependently selected from nitrogen, sulfur and oxygen;

[0180] wherein said ring or rings formed by R_(III-5) and R_(III-6), orR_(III-6) and R_(III-7), and/or R_(III-7) and R_(III-8) are optionallymono-, di- or tri-substituted independently with halo, (C₁-C₆)alkyl,(C₁-C₄)alkylsulfonyl, (C₂-C₆)alkenyl, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent optionally having from one to nine fluorines;

[0181] provided that the R_(III-5), R_(III-6), R_(III-7) and/orR_(III-8), as the case may be, that do not form at least one ring areeach independently hydrogen, halo, (C₁-C₆)alkoxy or (C₁-C₆)alkyl, said(C₁-C₆)alkyl optionally having from one to nine fluorines.

[0182] Compounds of Formula Ill are disclosed in commonly assignedpending U.S. Pat. No. 6,147,089, the complete disclosure of which isherein incorporated by reference.

[0183] In a preferred embodiment, the CETP inhibitor is selected fromone of the following compounds of Formula Ill:

[0184] [2R, 4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-2,3,4,6,7,8-hexahydro-cyclopenta[g]quinoline-1-carboxylicacid ethyl ester;

[0185] [6R, 8S]8-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-methyl-3,6,7,8-tetrahydro-1H-2-thia-5-aza-cyclopenta[b]naphthalene-5-carboxylicacid ethyl ester;

[0186] [6R, 8S]8-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-methyl-3,6,7,8-tetrahydro-2H-furo[2,3-g]quinoline-5-carboxylicacid ethyl ester;

[0187] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-3,4,6,8-tetrahydro-2H-furo[3,4-g]quinoline-1-carboxylicacid ethyl ester;

[0188] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-3,4,6,7,8,9-hexahydro-2H-benzo[g]quinoline-1-carboxylicacid propyl ester;

[0189] [7R,9S]9-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-methyl-1,2,3,7,8,9-hexahydro-6-aza-cyclopenta[a]naphthalene-6-carboxylicacid ethyl ester; and

[0190] [6S ,8R]6-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-8-methyl-1,2,3,6,7,8-hexahydro-9-aza-cyclopenta[a]naphthalene-9-carboxylicacid ethyl ester.

[0191] Another class of CETP inhibitors that finds utility with thepresent invention consists of4-carboxyamino-2-substituted-1,2,3,4,-tetrahydroquinolines, having theFormula IV

[0192] and pharmaceutically acceptable forms thereof;

[0193] wherein R_(IV-1) is hydrogen, Y_(IV), W_(IV)-X_(IV) orW_(IV)-Y_(IV);

[0194] wherein W_(IV) is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;

[0195] X_(IV) is —O—Y_(IV), —S—Y_(IV), —N(H)—Y_(IV) or —N—(Y_(IV))₂;

[0196] wherein Y_(IV) for each occurrence is independently Z_(IV) or afully saturated, partially unsaturated or fully unsaturated one to tenmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with one or twoheteroatoms selected independently from oxygen, sulfur and nitrogen andsaid carbon is optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with hydroxy, saidcarbon is optionally mono-substituted with oxo, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono-, or di-substituted with oxo, and said carbon chain is optionallymono-substituted with Z_(IV);

[0197] wherein Z_(IV) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

[0198] wherein said Z_(IV) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines;

[0199] R_(IV-2) is a partially saturated, fully saturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one or two heteroatoms selected independently from oxygen,sulfur and nitrogen wherein said carbon atoms are optionally mono-, di-or tri-substituted independently with halo, said carbon is optionallymono-substituted with oxo, said carbon is optionally mono-substitutedwith hydroxy, said sulfur is optionally mono- or di-substituted withoxo, said nitrogen is optionally mono- or di-substituted with oxo; orsaid R_(IV-2) is a partially saturated, fully saturated or fullyunsaturated three to seven membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen,wherein said R_(IV-2) ring is optionally attached through (C₁-C₄)alkyl;

[0200] wherein said R_(IV-2) ring is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, oxo or (C₁-C₆)alkyloxycarbonyl;

[0201] with the proviso that R_(IV-2) is not methyl;

[0202] R_(IV-3) is hydrogen or Q_(IV);

[0203] wherein Q_(IV) is a fully saturated, partially unsaturated orfully unsaturated one to six membered straight or branched carbon chainwherein the carbons other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(IV);

[0204] wherein V_(IV) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

[0205] wherein said V_(IV) substituent is optionally mono-, di-, tri-,or tetra-substituted independently with halo, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro,cyano, oxo, carboxamoyl, mono-N- or di-N,N-(C₁-C₆) alkylcarboxamoyl,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl or (C₂-C₆)alkenyl substituent is optionallymono-, di- or tri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl or (C₂-C₆)alkenyl substituents are also optionallysubstituted with from one to nine fluorines;

[0206] R_(IV-4) is Q_(IV-1) or V_(IV-1);

[0207] wherein Q_(IV-1) a fully saturated, partially unsaturated orfully unsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(IV-1);

[0208] wherein V_(IV-1) is a partially saturated, fully saturated orfully unsaturated three to six membered ring optionally having one totwo heteroatoms selected independently from oxygen, sulfur and nitrogen;

[0209] wherein said V_(IV-1) substituent is optionally mono-, di-, tri-,or tetra-substituted independently with halo, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, amino, nitro, cyano, (C₁-C₆)alkyloxycarbonyl, mono-N- ordi-N,N-(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituent isoptionally mono-substituted with oxo, said (C₁-C₆)alkyl substituent isalso optionally substituted with from one to nine fluorines;

[0210] wherein either R_(IV-3) must contain V_(IV) or R_(IV-4) mustcontain V_(IV-1);

[0211] R_(IV-5), R_(IV-6), R_(IV-7) and R_(IV-8) are each independentlyhydrogen, a bond, nitro or halo wherein said bond is substituted withT_(IV) or a partially saturated, fully saturated or fully unsaturated(C₁-C₁₂) straight or branched carbon chain wherein carbon, mayoptionally be replaced with one or two heteroatoms selectedindependently from oxygen, sulfur and nitrogen wherein said carbon atomsare optionally mono-, di- or tri-substituted independently with halo,said carbon is optionally mono-substituted with hydroxy, said carbon isoptionally mono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono- ordi-substituted with oxo, and said carbon is optionally mono-substitutedwith T_(IV);

[0212] wherein T_(IV) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, or,a bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

[0213] wherein said T_(IV) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines; and

[0214] wherein R_(IV-5) and R_(IV-6), or R_(IV-6) and R_(IV-7), and/orR_(IV-7) and R_(IV-8) may also be taken together and can form at leastone four to eight membered ring that is partially saturated or fullyunsaturated optionally having one to three heteroatoms independentlyselected from nitrogen, sulfur and oxygen;

[0215] wherein said ring or rings formed by R_(IV-5) and R_(IV-6), orR_(IV-6) and R_(IV-7), and/or R_(IV-7) and R_(IV-8) are optionallymono-, di- or tri-substituted independently with halo, (C₁-C₆)alkyl,(C₁-C₄)alkylsulfonyl, (C₂-C₆)alkenyl, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines; with the proviso that when R_(IV-2) is carboxyl or(C₁-C₄) alkylcarboxyl, then R_(IV-1) is not hydrogen.

[0216] Compounds of Formula IV are disclosed in commonly assigned U.S.Pat. No. 6,197,786, the complete disclosure of which is hereinincorporated by reference.

[0217] In a preferred embodiment, the CETP inhibitor is selected fromone of the following compounds of Formula IV:

[0218] [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-isopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0219] [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-chloro-2-cyclopropyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0220] [2S,4S]2-cyclopropyl-4-[(3,5-dichloro-benzyl)-methoxycarbonyl-amino]-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0221] [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester;

[0222] [2R,4R]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0223] [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0224] [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclobutyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester,

[0225] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0226] [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0227] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid 2-hydroxy-ethyl ester;

[0228] [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0229] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0230] [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid propyl ester;

[0231] and

[0232] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid propyl ester.

[0233] Another class of CETP inhibitors that finds utility with thepresent invention consists of 4-aminosubstituted-2-substituted-1,2,3,4,-tetrahydroquinolines, having theFormula V

[0234] and pharmaceutically acceptable forms thereof;

[0235] wherein R_(V-1) is Y_(V), W_(V)-X_(V) or W_(V)-Y_(V);

[0236] wherein W_(V) is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;

[0237] X_(V) is —O—Y_(V), —S—Y_(V), —N(H)—Y_(V) or —N—(Y_(V))₂;

[0238] wherein Y_(V) for each occurrence is independently Z_(V) or afully saturated, partially unsaturated or fully unsaturated one to tenmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with one or twoheteroatoms selected independently from oxygen, sulfur and nitrogen andsaid carbon is optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with hydroxy, saidcarbon is optionally mono-substituted with oxo, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono-, or di-substituted with oxo, and said carbon chain is optionallymono-substituted with Z_(V);

[0239] wherein Z_(V) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

[0240] wherein said Z_(V) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines;

[0241] R_(V-2) is a partially saturated, fully saturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one or two heteroatoms selected independently from oxygen,sulfur and nitrogen wherein said carbon atoms are optionally mono-, di-or tri-substituted independently with halo, said carbon is optionallymono-substituted with oxo, said carbon is optionally mono-substitutedwith hydroxy, said sulfur is optionally mono- or di-substituted withoxo, said nitrogen is optionally mono- or di-substituted with oxo; orsaid R_(V-2) is a partially saturated, fully saturated or fullyunsaturated three to seven membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen,wherein said R_(V-2) ring is optionally attached through (C₁-C₄)alkyl;

[0242] wherein said R_(V-2) ring is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, oxo or (C₁-C₆)alkyloxycarbonyl;

[0243] R_(V-3) is hydrogen or Q_(V);

[0244] wherein Q_(V) is a fully saturated, partially unsaturated orfully unsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono-, or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(V);

[0245] wherein V_(V) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

[0246] wherein said V_(V) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxamoyl, mono-N- or di-N,N-(C₁-C₆) alkylcarboxamoyl, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl or (C₂-C₆)alkenyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl or (C₂-C₆)alkenyl substituents are also optionallysubstituted with from one to nine fluorines;

[0247] R_(V-4) is cyano, formyl, W_(V-1)Q_(V-1), W_(V-1)V_(V-1),(C₁-C₄)alkylene V_(V-1) or V_(V-2);

[0248] wherein W_(V-1) is carbonyl, thiocarbonyl, SO or SO₂,

[0249] wherein Q_(V-1) a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons may optionally be replaced with one heteroatomselected from oxygen, sulfur and nitrogen and said carbon is optionallymono-, di- or tri-substituted independently with halo, said carbon isoptionally mono-substituted with hydroxy, said carbon is optionallymono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono-, ordi-substituted with oxo, and said carbon chain is optionallymono-substituted with V_(V-1);

[0250] wherein V_(V-1) is a partially saturated, fully saturated orfully unsaturated three to six membered ring optionally having one totwo heteroatoms selected independently from oxygen, sulfur and nitrogen,or a bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

[0251] wherein said V_(V-1) substituent is optionally mono-, di-, tri-,or tetra-substituted independently with halo, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, hydroxy, oxo, amino, nitro, cyano,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-substituted with oxo,said (C₁-C₆)alkyl substituent is also optionally substituted with fromone to nine fluorines;

[0252] wherein V_(V-2) is a partially saturated, fully saturated orfully unsaturated five to seven membered ring containing one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen;

[0253] wherein said V_(V-2) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₂)alkyl, (C₁-C₂)alkoxy,hydroxy, or oxo wherein said (C₁-C₂)alkyl optionally has from one tofive fluorines; and

[0254] wherein R_(V-4) does not include oxycarbonyl linked directly tothe C₄ nitrogen;

[0255] wherein either R_(V-3) must contain V_(V) or R_(V-4) must containV_(V-1);

[0256] R_(V-5), R_(V-6), R_(V-7) and R_(V-8) are independently hydrogen,a bond, nitro or halo wherein said bond is substituted with T_(V) or apartially saturated, fully saturated or fully unsaturated (C₁-C₁₂)straight or branched carbon chain wherein carbon may optionally bereplaced with one or two heteroatoms selected independently from oxygen,sulfur and nitrogen, wherein said carbon atoms are optionally mono-, di-or tri-substituted independently with halo, said carbon is optionallymono-substituted with hydroxy, said carbon is optionallymono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono- ordi-substituted with oxo, and said carbon chain is optionallymono-substituted with T_(V);

[0257] wherein T_(V) is a partially saturated, fully saturated or fullyunsaturated three to twelve membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

[0258] wherein said T_(V) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent also optionally has from one to nine fluorines;

[0259] wherein R_(V-5) and R_(V-6), or R_(V-6) and R_(V-7), and/orR_(V-7) and R_(V-8) may also be taken together and can form at least onering that is a partially saturated or fully unsaturated four to eightmembered ring optionally having one to three heteroatoms independentlyselected from nitrogen, sulfur and oxygen;

[0260] wherein said rings formed by R_(V-5) and R_(V-6), or R_(V-6) andR_(V-7), and/or R_(V-7) R_(V-8) are optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl,(C₁-C₄)alkylsulfonyl, (C₂-C₆)alkenyl, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent also optionally has from one to nine fluorines.

[0261] Compounds of Formula V are disclosed in commonly assigned U.S.Pat. No. 6,140,343, the complete disclosure of which is hereinincorporated by reference.

[0262] In a preferred embodiment, the CETP inhibitor is selected fromone of the following compounds of Formula V:

[0263] [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0264] [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid propyl ester;

[0265] [2S,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester;

[0266] [2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0267] [2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester,

[0268] [2S,4S]4-[1-(3,5-bis-trifluoromethyl-benzyl)-ureido]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0269] [2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0270] [2S,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0271] [2S,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid propyl ester;

[0272] [2S,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0273] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0274] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0275] [2S,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[0276] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0277] [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[0278] [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester; and

[0279] [2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

[0280] Another class of CETP inhibitors that finds utility with thepresent invention consists of cycloalkano-pyridines having the FormulaVI

[0281] and pharmaceutically acceptable forms thereof;

[0282] in which A_(VI) denotes an aryl containing 6 to 10 carbon atoms,which is optionally substituted with up to five identical or differentsubstituents in the form of a halogen, nitro, hydroxyl, trifluoromethyl,trifluoromethoxy or a straight-chain or branched alkyl, acyl,hydroxyalkyl or alkoxy containing up to 7 carbon atoms each, or in theform of a group according to the formula —NR_(VI-3)R_(VI-4), wherein

[0283] R_(VI-3) and R_(VI-4) are identical or different and denote ahydrogen, phenyl or a straight-chain or branched alkyl containing up to6 carbon atoms,

[0284] D_(VI) denotes an aryl containing 6 to 10 carbon atoms, which isoptionally substituted with a phenyl, nitro, halogen, trifluoromethyl ortrifluoromethoxy, or a radical according to the formulaR_(VI-5)-L_(VI-),

[0285] or R_(VI-9)-T_(VI)-V_(VI)-X_(VI), wherein

[0286] R_(VI-5), R_(VI-6) and R_(VI-9) denote, independently from oneanother, a cycloalkyl containing 3 to 6 carbon atoms, or an arylcontaining 6 to 10 carbon atom or a 5- to 7-membered, optionallybenzo-condensed, saturated or unsaturated, mono-, bi- or tricyclicheterocycle containing up to 4 heteroatoms from the series of S, Nand/or O, wherein the rings are optionally substituted, in the case ofthe nitrogen-containing rings also via the N function, with up to fiveidentical or different substituents in the form of a halogen,trifluoromethyl, nitro, hydroxyl, cyano, carboxyl, trifluoromethoxy, astraight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxyor alkoxycarbonyl containing up to 6 carbon atoms each, an aryl ortrifluoromethyl-substituted aryl containing 6 to 10 carbon atoms each,or an optionally benzo-condensed, aromatic 5- to 7-membered heterocyclecontaining up to 3 heteoatoms from the series of S, N and/or O, and/orin the form of a group according to the formula —OR_(VI-10),—SR_(VI-11), —SO₂R_(VI-12) or —NR_(VI-13)R_(VI-14), wherein

[0287] R_(VI-10), R_(VI-11) and R_(VI-12) denote, independently from oneanother, an aryl containing 6 to 10 carbon atoms, which is in turnsubstituted with up to two identical or different substituents in theform of a phenyl, halogen or a straight-chain or branched alkylcontaining up to 6 carbon atoms,

[0288] R_(VI-13) and R_(VI-14) are identical or different and have themeaning of R_(VI-3) and R_(VI-4) given above, or

[0289] R_(VI-5) and/or R_(VI-6) denote a radical according to theformula

[0290] R_(VI-7) denotes a hydrogen or halogen, and

[0291] R_(VI-8) denotes a hydrogen, halogen, azido, trifluoromethyl,hydroxyl, trifluoromethoxy, a straight-chain or branched alkoxy or alkylcontaining up to 6 carbon atoms each, or a radical according to theformula

—NR_(VI-15)R_(VI-16)

[0292] wherein

[0293] R_(VI-15) and R_(VI-16) are identical or different and have themeaning of R_(VI-3) and R_(VI-4) given above, or

[0294] R_(VI-7) and R_(VI-8) together form a radical according to theformula ═O or ═NR_(VI-17), wherein

[0295] R_(VI-17) denotes a hydrogen or a straight-chain or branchedalkyl, alkoxy or acyl containing up to 6 carbon atoms each,

[0296] L_(VI) denotes a straight-chain or branched alkylene oralkenylene chain containing up to 8 carbon atoms each, which areoptionally substituted with up to two hydroxyl groups,

[0297] T_(VI) and X_(VI) are identical or different and denote astraight-chain or branched alkylene chain containing up to 8 carbonatoms, or

[0298] T_(VI) or X_(VI) denotes a bond,

[0299] V_(VI) denotes an oxygen or sulfur atom or an —NR_(VI-18) group,wherein

[0300] R_(VI-18) denotes a hydrogen or a straight-chain or branchedalkyl containing up to 6 carbon atoms or a phenyl,

[0301] E_(VI) denotes a cycloalkyl containing 3 to 8 carbon atoms, or astraight-chain or branched alkyl containing up to 8 carbon atoms, whichis optionally substituted with a cycloalkyl containing 3 to 8 carbonatoms or a hydroxyl, or a phenyl, which is optionally substituted with ahalogen or trifluoromethyl,

[0302] R_(VI-1) and R_(VI-2) together form a straight-chain or branchedalkylene chain containing up to 7 carbon atoms, which must besubstituted with a carbonyl group and/or a radical according to theformula

[0303] wherein

[0304] a and b are identical or different and denote a number equaling1, 2 or 3,

[0305] R_(VI-19) denotes a hydrogen atom, a cycloalkyl containing 3 to 7carbon atoms, a straight-chain or branched silylalkyl containing up to 8carbon atoms, or a straight-chain or branched alkyl containing up to 8carbon atoms, which is optionally substituted with a hydroxyl, astraight-chain or a branched alkoxy containing up to 6 carbon atoms or aphenyl, which may in turn be substituted with a halogen, nitro,trifluoromethyl, trifluoromethoxy or phenyl or tetrazole-substitutedphenyl, and an alkyl that is optionally substituted with a groupaccording to the formula —OR_(VI-22), wherein

[0306] R_(VI-22) denotes a straight-chain or branched acyl containing upto 4 carbon atoms or benzyl, or

[0307] R_(VI-19) denotes a straight-chain or branched acyl containing upto 20 carbon atoms or benzoyl, which is optionally substituted with ahalogen, trifluoromethyl, nitro or trifluoromethoxy, or a straight-chainor branched fluoroacyl containing up to 8 carbon atoms,

[0308] R_(VI-20) and R_(VI-21) are identical or different and denote ahydrogen, phenyl or a straight-chain or branched alkyl containing up to6 carbon atoms, or

[0309] R_(VI-20) and R_(VI-21) together form a 3- to 6-memberedcarbocyclic ring, and a the carbocyclic rings formed are optionallysubstituted, optionally also geminally, with up to six identical ordifferent substituents in the form of trifluoromethyl, hydroxyl,nitrile, halogen, carboxyl, nitro, azido, cyano, cycloalkyl orcycloalkyloxy containing 3 to 7 carbon atoms each, a straight-chain orbranched alkoxycarbonyl, alkoxy or alkylthio containing up to 6 carbonatoms each, or a straight-chain or branched alkyl containing up to 6carbon atoms, which is in turn substituted with up to two identical ordifferent substituents in the form of a hydroxyl, benzyloxy,trifluoromethyl, benzoyl, a straight-chain or branched alkoxy, oxyacylor carboxyl containing up to 4 carbon atoms each and/or a phenyl, whichmay in turn be substituted with a halogen, trifluoromethyl ortrifluoromethoxy, and/or the carbocyclic rings formed are optionallysubstituted, also geminally, with up to five identical or differentsubstituents in the form of a phenyl, benzoyl, thiophenyl orsulfonylbenzyl, which in turn are optionally substituted with a halogen,trifluoromethyl, trifluoromethoxy or nitro, and/or optionally in theform of a radical according to the formula

[0310] wherein

[0311] c is a number equaling 1, 2, 3 or 4,

[0312] d is a number equaling 0 or 1,

[0313] R_(VI-23) and R_(VI-24) are identical or different and denote ahydrogen, cycloalkyl containing 3 to 6 carbon atoms, a straight-chain orbranched alkyl containing up to 6 carbon atoms, benzyl or phenyl, whichis optionally substituted with up to two identical or differentsubstituents in the form of halogen, trifluoromethyl, cyano, phenyl ornitro, and/or the carbocyclic rings formed are optionally substitutedwith a spiro-linked radical according to the formula

[0314] wherein

[0315] W_(VI) denotes either an oxygen atom or a sulfur atom,

[0316] Y_(VI) and Y′_(VI) together form a 2- to 6-memberedstraight-chain or branched alkylene chain,

[0317] e is a number equaling 1, 2, 3, 4, 5, 6 or 7,

[0318] f is a number equaling 1 or 2,

[0319] R_(VI-25), R_(VI-26), R_(VI-27), R_(VI-28), R_(VI-29), R_(VI-30)and R_(VI-31) are identical or different and denote a hydrogen,trifluoromethyl, phenyl, halogen or a straight-chain or branched alkylor alkoxy containing up to 6 carbon atoms each, or

[0320] R_(VI-25) and R_(VI-26) or R_(VI-27) and R_(VI-28) each togetherdenote a straight-chain or branched alkyl chain containing up to 6carbon atoms or

[0321] R_(VI-25) and R_(VI-26) or R_(VI-27) and R_(VI-28) each togetherform a radical according to the formula

[0322] wherein

[0323] W_(VI) has the meaning given above,

[0324] g is a number equaling 1, 2, 3, 4, 5, 6 or 7,

[0325] R_(VI-32) and R_(VI-33) together form a 3- to 7-memberedheterocycle, which contains an oxygen or sulfur atom or a groupaccording to the formula SO, S₂ or —NR_(VI-34),

[0326] wherein

[0327] R_(VI-34) denotes a hydrogen atom, a phenyl, benzyl, or astraight-chain or branched alkyl containing up to 4 carbon atoms, andsalts and N oxides thereof, with the exception of 5(6H)-quinolones,3-benzoyl-7,8-dihydro-2,7,7-trimethyl-4-phenyl.

[0328] Compounds of Formula VI are disclosed in European PatentApplication No. EP 818448 A1, the complete disclosure of which is hereinincorporated by reference.

[0329] In a preferred embodiment, the CETP inhibitor is selected fromone of the following compounds of Formula VI:

[0330]2-cyclopentyl-4-(4-fluorophenyl)-7,7-dimethyl-3-(4-trifluoromethylbenzoyl)-4,6,7,8-tetrahydro-1H-quinolin-5-one;

[0331]2-cyclopentyl-4-(4-fluorophenyl)-7,7-dimethyl-3-(4-trifluoromethylbenzoyl)-7,8-dihydro-6H-quinolin-5-one;

[0332][2-cyclopentyl-4-(4-fluorophenyl)-5-hydroxy-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-trifluoromethylphenyl)-methanone;

[0333][5-(t-butyldimethylsilanyloxy)-2-cyclopentyl-4-(4-fluorophenyl)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-trifluoromethylphenyl)-methanone;

[0334][5-(t-butyldimethylsilanyloxy)-2-cyclopentyl-4-(4-fluorophenyl)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-trifluoromethylphenyl)-methanol;

[0335]5-(t-butyldimethylsilanyloxy)-2-cyclopentyl-4-(4-fluorophenyl)-3-[fluoro-(4-trifluoromethylphenyl)-methyl]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline;

[0336]2-cyclopentyl-4-(4-fluorophenyl)-3-[fluoro-(4-trifluoromethylphenyl)-methyl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol.

[0337] Another class of CETP inhibitors that finds utility with thepresent invention consists of substituted-pyridines having the FormulaVII

[0338] and pharmaceutically acceptable forms thereof, wherein

[0339] R_(VII-2) and R_(VII-6) are independently selected from the groupconsisting of hydrogen, hydroxy, alkyl, fluorinated alkyl, fluorinatedaralkyl, chlorofluorinated alkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, alkoxy, alkoxyalkyl, and alkoxycarbonyl; provided that atleast one of R_(VII-2) and R_(VII-6) is fluorinated alkyl,chlorofluorinated alkyl or alkoxyalkyl;

[0340] R_(VII-3) is selected from the group consisting of hydroxy,amido, arylcarbonyl, heteroarylcarbonyl, hydroxymethyl—CHO,—CO₂R_(VII-7), wherein R_(VII-7) is selected from the groupconsisting of hydrogen, alkyl and cyanoalkyl; and

[0341] wherein R_(VII-15a) is selected from the group consisting ofhydroxy, hydrogen, halogen, alkylthio, alkenylthio, alkynylthio,arylthio, heteroarylthio, heterocyclylthio, alkoxy, alkenoxy, alkynoxy,aryloxy, heteroaryloxy and heterocyclyloxy, and

[0342] R_(VII-16a) is selected from the group consisting of alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl,and heterocyclyl, arylalkoxy, trialkylsilyloxy;

[0343] R_(VII-4) is selected from the group consisting of hydrogen,hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl,cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl,heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl,hetereoarylalkenyl, heterocyclylalkenyl, alkoxy, alkenoxy, alkynoxy,aryloxy, heteroaryloxy, heterocyclyloxy, alkanoyloxy, alkenoyloxy,alkynoyloxy, aryloyloxy, heteroaroyloxy, heterocyclyloyloxy,alkoxycarbonyl, alkenoxycarbonyl, alkynoxycarbonyl, aryloxycarbonyl,heteroaryloxycarbonyl, heterocyclyloxycarbonyl, thio, alkylthio,alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio,cycloalkylthio, cycloalkenylthio, alkylthioalkyl, alkenylthioalkyl,alkynylthioalkyl, arylthioalkyl, heteroarylthioalkyl,heterocyclylthioalkyl, alkylthioalkenyl, alkenylthioalkenyl,alkynylthioalkenyl, arylthioalkenyl, heteroarylthioalkenyl,heterocyclythioalkenyl, alkylamino, alkenylamino, alkynylamino,arylamino, heteroarylamino, heterocyclylamino, aryldialkylamino,diarylamino, diheteroarylamino, alkylarylamino, alkylheteroarylamino,arylheteroarylamino, trialkylsilyl, trialkenylsilyl, triarylsilyl,—CO(O)N(R_(VII-8a)R_(VII-8b)), wherein R_(VII-8a) and R_(VII-8b) areindependently selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl and heterocyclyl,—SO₂R_(VII-9), whereinR_(VII-9) is selected from the group consisting of hydroxy, alkyl,alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl,—OP(O)(OR_(VII-10a)) (OR_(VII-10b)), wherein R_(VII-10a) and R_(VII-10b)are independently selected from the group consisting of hydrogen,hydroxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, and—OP(S) (OR_(VII-11a)) (OR_(VII-11b)), wherein R_(VII-11a) andR_(VII-11b) are independently selected from the group consisting ofalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;

[0344] R_(VII-5) is selected from the group consisting of hydrogen,hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl,alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy,alkylcarbonyloxyalkyl, alkenylcarbonyloxyalkyl, alkynylcarbonyloxyalkyl,arylcarbonyloxyalkyl, heteroarylcarbonyloxyalkyl,heterocyclylcarbonyloxyalkyl, cycloalkylalkyl, cycloalkenylalkyl,aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl,cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl,alkylthioalkyl, cycloalkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl,arylthioalkyl, heteroarylthioalkyl, heterocyclylthioalkyl,alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl,arylthioalkenyl, heteroarylthioalkenyl, heterocyclylthioalkenyl,alkoxyalkyl, alkenoxyalkyl, alkynoxylalkyl, aryloxyalkyl,heteroaryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkenyl,alkenoxyalkenyl, alkynoxyalkenyl, aryloxyalkenyl, heteroaryloxyalkenyl,heterocyclyloxyalkenyl, cyano, hydroxymethyl, —CO₂R_(VII-14), whereinR_(VII-14) is selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl and heterocyclyl;

[0345] wherein R_(VII-15b) is selected from the group consisting ofhydroxy, hydrogen, halogen, alkylthio, alkenylthio, alkynylthio,arylthio, heteroarylthio, heterocyclylthio, alkoxy, alkenoxy, alkynoxy,aryloxy, heteroaryloxy, heterocyclyloxy, aroyloxy, and alkylsulfonyloxy,and

[0346] R_(VII-16b) is selected form the group consisting of alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkoxy, andtrialkylsilyloxy;

[0347] wherein R_(VII-17) and R_(VII-18) are independently selected fromthe group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl,heteroaryl and heterocyclyl;

[0348] wherein R_(VII-19) is selected from the group consisting ofalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,—SR_(VII-20), —OR_(VII-21), and —R_(VII-22)CO₂R_(VII-23), wherein

[0349] R_(VII-20) is selected from the group consisting of alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aminoalkyl,aminoalkenyl, aminoalkynyl, aminoaryl, aminoheteroaryl,aminoheterocyclyl, alkylheteroarylamino, arylheteroarylamino,

[0350] R_(VII-21) is selected from the group consisting of alkyl,alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl,

[0351] R_(VII-22) is selected from the group consisting of alkylene orarylene, and

[0352] R_(VII-23) is selected from the group consisting of alkyl,alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;

[0353] wherein R_(VII-24) is selected from the group consisting ofhydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, aralkyl, aralkenyl, and aralkynyl;

[0354] wherein R_(VII-25) is heterocyclylidenyl;

[0355] wherein R_(VII-26) and R_(VII-27) are independently selected fromthe group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl,aryl, heteroaryl, and heterocyclyl;

[0356] wherein R_(VII-28) and R_(VII-29) are independently selected fromthe group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl,aryl, heteroaryl, and heterocyclyl;

[0357] wherein R_(VII-30) and R_(VII-31) are independently alkoxy,alkenoxy, alkynoxy, aryloxy, heteroaryloxy, and heterocyclyloxy; and

[0358] wherein R_(VII-32) and R_(VI-33) are independently selected fromthe group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl,aryl, heteroaryl, and heterocyclyl;

[0359] wherein R_(VII-36) is selected from the group consisting ofalkyl, alkenyl, aryl, heteroaryl and heterocyclyl;

[0360] wherein R_(VII-37) and R_(VI-38) are independently selected fromthe group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl,aryl, heteroaryl, and heterocyclyl;

[0361] wherein R_(VII-39) is selected from the group consisting ofhydrogen, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy,heterocyclyloxy, alkylthio, alkenylthio, alkynylthio, arylthio,heteroarylthio and heterocyclylthio, and

[0362] R_(VII-40) is selected from the group consisting of haloalkyl,haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, haloheterocyclyl,cycloalkyl, cycloalkenyl, heterocyclylalkoxy, heterocyclylalkenoxy,heterocyclylalkynoxy, alkylthio, alkenylthio, alkynylthio, arylthio,heteroarylthio and heterocyclylthio;

—N═_(VII-41),

[0363] wherein R_(VII-41) is heterocyclylidenyl;

[0364] wherein R_(VII-42) is selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl,and

[0365] R_(VII-43) is selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, haloaryl,haloheteroaryl, and haloheterocyclyl;

[0366] wherein R_(VII-44) is selected from the group consisting ofhydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl andheterocyclyl;

—N═S═O:

—N═C═S;

—N═C═O:

—N₃;

—SR_(VII-45)

[0367] wherein R_(VII-45) is selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl,haloheterocyclyl, heterocyclyl, cycloalkylalkyl, cycloalkenylalkyl,aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl,cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl,alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl,arylthioalkyl,heteroarylthioalkyl, heterocyclylthioalkyl,alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl,arylthioalkenyl, heteroarylthioalkenyl, heterocyclylthioalkenyl,aminocarbonylalkyl, aminocarbonylalkenyl, aminocarbonylalkynyl,aminocarbonylaryl, aminocarbonylheteroaryl, andaminocarbonylheterocyclyl,

—SR_(VII-46), and —CH₂R_(VII-47),

[0368] wherein R_(VII-46) is selected from the group consisting ofalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, and

[0369] R_(VII-47) is selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl; and

[0370] wherein R_(VII-48) is selected from the group consisting ofhydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl andheterocyclyl, and

[0371] R_(VII-49) is selected from the group consisting of alkoxy,alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, haloalkyl,haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl and haloheterocyclyl;

[0372] wherein R_(VII-50) is selected from the group consisting ofhydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclyl, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy andheterocyclyloxy;

[0373] wherein R_(VII-51) is selected from the group consisting ofalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, haloalkyl,haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl and haloheterocyclyl;and

[0374] wherein R_(VII-53) is selected from the group consisting ofalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;

[0375] provided that when R_(VII-5) is selected from the groupconsisting of heterocyclylalkyl and heterocyclylalkenyl, theheterocyclyl radical of the corresponding heterocyclylalkyl orheterocyclylalkenyl is other than δ-lactone; and

[0376] provided that when R_(VII-4) is aryl, heteroaryl or heterocyclyl,and one of R_(VII-2) and R_(VII-6) is trifluoromethyl, then the other ofR_(VII-2) and R_(VII-6) is difluoromethyl.

[0377] Compounds of Formula VII are disclosed in WO 9941237-A1, thecomplete disclosure of which is incorporated by reference.

[0378] In a preferred embodiment, the CETP inhibitor is selected fromthe following compounds of Formula VII:

[0379] dimethyl5,5′-dithiobis[2-difluoromethyl-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridine-carboxylate].

[0380] Another class of CETP inhibitors that finds utility with thepresent invention consists of substituted pyridines and biphenyls havingthe Formula VIII

[0381] and pharmaceutically acceptable forms thereof, in which

[0382] A_(VIII) stands for aryl with 6 to 10 carbon atoms, which isoptionally substituted up to 3 times in an identical manner ordifferently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, orby straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbonatoms each, or by a group of the formula

—NR_(VIII-1)R_(VIII-2), wherein

[0383] R_(VIII-1) and R_(VIII-2) are identical or different and denotehydrogen, phenyl, or straight-chain or branched alkyl with up to 6carbon atoms,

[0384] D_(VIII) stands for straight-chain or branched alkyl with up to 8carbon atoms, which is substituted by hydroxy,

[0385] E_(VIII) and L_(VIII) are either identical or different and standfor straight-chain or branched alkyl with up to 8 carbon atoms, which isoptionally substituted by cycloalkyl with 3 to 8 carbon atoms, or standsfor cycloalkyl with 3 to 8 carbon atoms, or

[0386] E_(VIII) has the above-mentioned meaning and

[0387] L_(VIII) in this case stands for aryl with 6 to 10 carbon atoms,which is optionally substituted up to 3 times in an identical manner ordifferently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, orby straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbonatoms each, or by a group of the formula

—NR_(VIII-3)R_(VIII-4), wherein

[0388] R_(VIII-3) and R_(VIII-4) are identical or different and have themeaning given above for R_(VIII-1) and R_(VIII-2), or

[0389] E_(VIII) stands for straight-chain or branched alkyl with up to 8carbon atoms, or stands for aryl with 6 to 10 carbon atoms, which isoptionally substituted up to 3 times in an identical manner ordifferently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, orby straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbonatoms each, or by a group of the formula

—NR_(VIII-5)R_(VIII-6), wherein

[0390] R_(VIII-5) and R_(VIII-6) are identical or different and have themeaning given above for R_(VIII-1) and R_(VIII-2), and

[0391] L_(VIII) in this case stands for straight-chain or branchedalkoxy with up to 8 carbon atoms or for cycloalkyloxy with 3 to 8 carbonatoms,

[0392] T_(VIII) stands for a radical of the formula

[0393] wherein

[0394] R_(VIII-7) and R_(VIII-8) are identical or different and denotecycloalkyl with 3 to 8 carbon atoms, or aryl with 6 to 10 carbon atoms,or denote a 5- to 7-member aromatic, optionally benzo-condensed,heterocyclic compound with up to 3 heteroatoms from the series S, Nand/or O, which are optionally substituted up to 3 times in an identicalmanner or differently by trifluoromethyl, trifluoromethoxy, halogen,hydroxy, carboxyl, by straight-chain or branched alkyl, acyl, alkoxy, oralkoxycarbonyl with up to 6 carbon atoms each, or by phenyl, phenoxy, orthiophenyl, which can in turn be substituted by halogen,trifluoromethyl, or trifluoromethoxy, and/or the rings are substitutedby a group of the formula

—NR_(VIII-11)R_(VIII-2), wherein

[0395] R_(VIII-11) and R_(VIII-12) are identical or different and havethe meaning given above for R_(VIII-1) and R_(VIII-2),

[0396] X_(VIII) denotes a straight or branched alkyl chain or alkenylchain with 2 to 10 carbon atoms each, which are optionally substitutedup to 2 times by hydroxy,

[0397] R_(VIII-9) denotes hydrogen, and

[0398] R_(VIII-10) denotes hydrogen, halogen, azido, trifluoromethyl,hydroxy, mercapto, trifluoromethoxy, straight-chain or branched alkoxywith up to 5 carbon atoms, or a radical of the formula

—NR_(VIII-13)R_(VIII-14), wherein

[0399] R_(VIII-13) and R_(VIII-14) are identical or different and havethe meaning given above for R_(VIII-1) and R_(VIII-2), or

[0400] R_(VIII-9) and R_(VIII-10) form a carbonyl group together withthe carbon atom.

[0401] Compounds of Formula VIII are disclosed in WO 9804528, thecomplete disclosure of which is incorporated by reference.

[0402] Another class of CETP inhibitors that finds utility with thepresent invention consists of substituted 1,2,4-triazoles having theFormula IX

[0403] and pharmaceutically acceptable forms thereof;

[0404] wherein R_(IX-1) is selected from higher alkyl, higher alkenyl,higher alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl,alkylthioalkyl, arylthioalkyl, and cycloalkylalkyl;

[0405] wherein R_(IX-2) is selected from aryl, heteroaryl, cycloalkyl,and cycloalkenyl,

[0406] wherein R_(IX-2) is optionally substituted at a substitutableposition with one or more radicals independently selected from alkyl,haloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxy, halo,aryloxy, aralkyloxy, aryl, aralkyl, aminosulfonyl, amino, monoalkylaminoand dialkylamino; and

[0407] wherein R_(IX-3) is selected from hydrido, —SH and halo; providedR_(IX-2) cannot be phenyl or 4-methylphenyl when R_(IX-1) is higheralkyl and when R_(IX-3) is —SH.

[0408] Compounds of Formula IX are disclosed in WO 9914204, the completedisclosure of which is incorporated by reference.

[0409] In a preferred embodiment, the CETP inhibitor is selected fromthe following compounds of Formula IX:

[0410]2,4-dihydro-4-(3-methoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0411]2,4-dihydro-4-(2-fluorophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0412]2,4-dihydro-4-(2-methylphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0413]2,4-dihydro-4-(3-chlorophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0414]2,4-dihydro-4-(2-methoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0415]2,4-dihydro-4-(3-methylphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0416] 4-cyclohexyl-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0417] 2,4-dihydro-4-(3-pyridyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0418]2,4-dihydro-4-(2-ethoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0419]2,4-dihydro-4-(2,6-dimethylphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0420]2,4-dihydro-4-(4-phenoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0421]4-(1,3-benzodioxol-5-yl)-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0422]4-(2-chlorophenyl)-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0423]2,4-dihydro-4-(4-methoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0424]2,4-dihydro-5-tridecyl-4-(3-trifluoromethylphenyl)-3H-1,2,4-triazole-3-thione;

[0425]2,4-dihydro-5-tridecyl-4-(3-fluorophenyl)-3H-1,2,4-triazole-3-thione;

[0426]4-(3-chloro-4-methylphenyl)-2.4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0427]2,4-dihydro-4-(2-methylthiophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0428]4-(4-benzyloxyphenyl)-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0429] 2,4-dihydro-4-(2-naphthyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0430]2,4-dihydro-5-tridecyl-4-(4-trifluoromethylphenyl)-3H-1,2,4-triazole-3-thione;

[0431] 2,4-dihydro-4-(1-naphthyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0432]2,4-dihydro-4-(3-methylthiophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0433]2,4-dihydro-4-(4-methylthiophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0434]2,4-dihydro-4-(3,4-dimethoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0435]2,4-dihydro-4-(2,5-dimethoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0436]2,4-dihydro-4-(2-methoxy-5-chlorophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0437]4-(4-aminosulfonylphenyl)-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;

[0438]2,4-dihydro-5-dodecyl-4-(3-methoxyphenyl)-3H-1,2,4-triazole-3-thione;

[0439]2,4-dihydro-4-(3-methoxyphenyl)-5-tetradecyl-3H-1,2,4-triazole-3-thione;

[0440]2,4-dihydro-4-(3-methoxyphenyl)-5-undecyl-3H-1,2,4-triazole-3-thione;

[0441] and

[0442]2,4-dihydro-(4-methoxyphenyl)-5-pentadecyl-3H-1,2,4-triazole-3-thione.

[0443] Another class of CETP inhibitors that finds utility with thepresent invention consists of hetero-tetrahydroquinolines having theFormula X

[0444] N-oxides of said compounds, and pharmaceutically acceptable formsthereof; in which

[0445] A_(X) represents cycloalkyl with 3 to 8 carbon atoms or a 5- to7-membered, saturated, partially saturated or unsaturated, optionallybenzo-condensed heterocyclic ring containing up to 3 heteroatoms fromthe series comprising S, N and/or O, that in case of a saturatedheterocyclic ring is bonded to a nitrogen function, optionally bridgedover it, and in which the aromatic systems mentioned above areoptionally substituted up to 5-times in an identical or differentsubstituents in the form of halogen, nitro, hydroxy, trifluoromethyl,trifluoromethoxy or by a straight-chain or branched alkyl, acyl,hydroxyalkyl or alkoxy each having up to 7 carbon atoms or by a group ofthe formula

—NR_(X-3)R_(X-4),

[0446] in which

[0447] R_(X-33) and R_(X-4) are identical or different and denotehydrogen, phenyl or straight-chain or branched alkyl having up to 6carbon atoms,

[0448] or

[0449] A_(X) represents a radical of the formula

[0450] D_(X) represents an aryl having 6 to 10 carbon atoms, that isoptionally substituted by phenyl, nitro, halogen, trifluormethyl ortrifluormethoxy, or it represents a radical of the formula

[0451] in which

[0452] R_(X-5), R_(X-6) and R_(X-9) independently of one another denotecycloalkyl having 3 to 6 carbon atoms, or an aryl having 6 to 10 carbonatoms or a 5- to 7-membered aromatic, optionally benzo-condensedsaturated or unsaturated, mono-, bi-, or tricyclic heterocyclic ringfrom the series consisting of S, N and/or O, in which the rings aresubstituted, optionally, in case of the nitrogen containing aromaticrings via the N function, with up to 5 identical or differentsubstituents in the form of halogen, trifluoromethyl, nitro, hydroxy,cyano, carbonyl, trifluoromethoxy, straight straight-chain or branchedacyl, alkyl, alkylthio, alkylalkoxy, alkoxy, or alkoxycarbonyl eachhaving up to 6 carbon atoms, by aryl or trifluoromethyl-substituted aryleach having 6 to 10 carbon atoms or by an, optionally benzo-condensed,aromatic 5- to 7-membered heterocyclic ring having up to 3 heteroatomsfrom the series consisting of S, N, and/or O, and/or substituted by agroup of the formula —OR_(X-10), 13 SR_(X-11), SO₂R_(X-12) or—NR_(X-13)R_(X-14),

[0453] in which

[0454] R_(X-10) R_(X-11) and R_(X-12) independently from each otherdenote aryl having 6 to 10 carbon atoms, which is in turn substitutedwith up to 2 identical or different substituents in the form of phenyl,halogen or a straight-chain or branched alkyl having up to 6 carbonatoms,

[0455] R_(X-13) and R_(X-14) are identical or different and have themeaning of R_(X-3) and R_(X-4) indicated above,

[0456] or

[0457] R_(X-5) and/or R_(X-6) denote a radical of the formula

[0458] R_(X-7) denotes hydrogen or halogen, and

[0459] R_(X-8) denotes hydrogen, halogen, azido, trifluoromethyl,hydroxy, trifluoromethoxy, straight-chain or branched alkoxy or alkylhaving up to 6 carbon atoms or a radical of the formula—NR_(X-15)R_(X-16), in which

[0460] R_(X-15) and R_(X-16) are identical or different and have themeaning of R_(X-3) and R_(X-4) indicated above,

[0461] or

[0462] R_(X-7) and R_(X-8) together form a radical of the formula ═O or═NR_(X-17),

[0463] in which

[0464] R_(X-17) denotes hydrogen or straight chain or branched alkyl,alkoxy or acyl having up to 6 carbon atoms,

[0465] L_(X) denotes a straight chain or branched alkylene or alkenylenechain having up to 8 carbon atoms, that are optionally substituted withup to 2 hydroxy groups,

[0466] T_(X) and X_(X) are identical or different and denote a straightchain or branched alkylene chain with up to 8 carbon atoms

[0467] or

[0468] T_(X) or X_(X) denotes a bond,

[0469] V_(X) represents an oxygen or sulfur atom or an —NR_(X-18)-group,in which

[0470] R_(X-18) denotes hydrogen or straight chain or branched alkylwith up to 6 carbon atoms or phenyl,

[0471] E_(X) represents cycloalkyl with 3 to 8 carbon atoms, or straightchain or branched alkyl with up to 8 carbon atoms, that is optionallysubstituted by cycloalkyl with 3 to 8 carbon atoms or hydroxy, orrepresents a phenyl, that is optionally substituted by halogen ortrifluoromethyl,

[0472] R_(X-1) and R_(X-2) together form a straight-chain or branchedalkylene chain with up to 7 carbon atoms, that must be substituted bycarbonyl group and/or by a radical with the formula

[0473] in which a and b are identical or different and denote a numberequaling 1,2, or 3,

[0474] R_(X-19) denotes hydrogen, cycloalkyl with 3 up to 7 carbonatoms, straight chain or branched silylalkyl with up to 8 carbon atomsor straight chain or branched alkyl with up to 8 carbon atoms, that areoptionally substituted by hydroxyl, straight chain or branched alkoxywith up to 6 carbon atoms or by phenyl, which in turn might besubstituted by halogen, nitro, trifluormethyl, trifluoromethoxy or byphenyl or by tetrazole-substituted phenyl, and alkyl, optionally besubstituted by a group with the formula —OR_(X-22),

[0475] in which

[0476] R_(X-22) denotes a straight chain or branched acyl with up to 4carbon atoms or benzyl,

[0477] or

[0478] R_(X-19) denotes straight chain or branched acyl with up to 20carbon atoms or benzoyl, that is optionally substituted by halogen,trifluoromethyl, nitro or trifluoromethoxy, or it denotes straight chainor branched fluoroacyl with up to 8 carbon atoms and 9 fluorine atoms,

[0479] R_(X-20) and R_(X-21) are identical or different and denotehydrogen, phenyl or straight chain or branched alkyl with up to 6 carbonatoms,

[0480] or

[0481] R_(X-20) and R_(X-21) together form a 3- to 6- memberedcarbocyclic ring, and the carbocyclic rings formed are optionallysubstituted, optionally also geminally, with up to six identical ordifferent substituents in the form of triflouromethyl, hydroxy, nitrile,halogen, carboxyl, nitro, azido, cyano, cycloalkyl or cycloalkyloxy with3 to 7 carbon atoms each, by straight chain or branched alkoxycarbonyl,alkoxy or alkylthio with up to 6 carbon atoms each or by straight chainor branched alkyl with up to 6 carbon atoms, which in turn issubstituted with up to 2 identically or differently by hydroxyl,benzyloxy, trifluoromethyl, benzoyl, straight chain or branched alkoxy,oxyacyl or carbonyl with up to 4 carbon atoms each and/or phenyl, whichmay in turn be substituted with a halogen, trifuoromethyl ortrifluoromethoxy, and/or the formed carbocyclic rings are optionallysubstituted, also geminally, with up to 5 identical or differentsubstituents in the form of phenyl, benzoyl, thiophenyl orsulfonylbenzyl, which in turn are optionally substituted by halogen,trifluoromethyl, trifluoromethoxy or nitro, and/or optionally aresubstituted by a radical with the formula

[0482] in which

[0483] c denotes a number equaling 1, 2, 3, or 4,

[0484] d denotes a number equaling 0 or 1,

[0485] R_(X-23) and R_(X-24) are identical or different and denotehydrogen, cycloalkyl with 3 to 6 carbon atoms, straight chain orbranched alkyl with up to 6 carbon atoms, benzyl or phenyl, that isoptionally substituted with up to 2 identically or differently byhalogen, trifluoromethyl, cyano, phenyl or nitro, and/or the formedcarbocyclic rings are substituted optionally by a spiro-linked radicalwith the formula

[0486] in which

[0487] W_(X) denotes either an oxygen or a sulfur atom

[0488] Y_(X) and Y′_(X) together form a 2 to 6 membered straight chainor branched alkylene chain,

[0489] e denotes a number equaling 1, 2, 3, 4, 5, 6, or 7,

[0490] f denotes a number equaling 1 or 2,

[0491] R_(X-25), R_(X-26), R_(X-27), R_(X-28), R_(X-29), R_(X-30) andR_(X-31) are identical or different and denote hydrogen,trifluoromethyl, phenyl, halogen or straight chain or branched alkyl oralkoxy with up to 6 carbon atoms each,

[0492] or

[0493] R_(X-25) and R_(X-26) or R_(X-27) and R_(X-28) respectively formtogether a straight chain or branched alkyl chain with up to 6 carbonatoms,

[0494] or

[0495] R_(X-25) and R_(X-26) or R_(X-27) and R_(X-28) each together forma radical with the formula

[0496] in which

[0497] W_(X) has the meaning given above,

[0498] g denotes a number equaling 1, 2, 3, 4, 5, 6, or 7,

[0499] R_(X-32) and R_(X-33) form together a 3- to 7- memberedheterocycle, which contains an oxygen or sulfur atom or a group with theformula SO, SO₂ or π—NR_(X-34), in which

[0500] R_(X-34) denotes hydrogen, phenyl, benzyl or straight or branchedalkyl with up to 4 carbon atoms.

[0501] Compounds of Formula X are disclosed in WO 9914215, the completedisclosure of which is incorporated by reference.

[0502] In a preferred embodiment, the CETP inhibitor is selected fromthe following compounds of Formula X:

[0503]2-cyclopentyl-5-hydroxy-7,7-dimethyl-4-(3-thienyl)-3-(4-trifluoromethylbenxoyl)-5,6,7,8-tetrahydroquinoline;

[0504]2-cyclopentyl-3-[fluoro-(4-trifluoromethylphenyl)methyl]-5-hydroxy-7,7-dimethyl-4-(3-thienyl)-5,6,7,8-tetrahydroquinoline;and

[0505]2-cyclopentyl-5-hydroxy-7,7-dimethyl-4-(3-thienyl)-3-(trifluoromethylbenxyl)-5,6,7,8-tetrahydroquinoline.

[0506] Another class of CETP inhibitors that finds utility with thepresent invention consists of substituted tetrahydro naphthalines andanalogous compounds having the Formula XI

[0507] and pharmaceutically acceptable forms thereof, in which

[0508] A_(XI) stands for cycloalkyl with 3 to 8 carbon atoms, or standsfor aryl with 6 to 10 carbon atoms, or stands for a 5- to 7-membered,saturated, partially unsaturated or unsaturated, possiblybenzocondensated, heterocycle with up to 4 heteroatoms from the seriesS, N and/or O, where aryl and the heterocyclic ring systems mentionedabove are substituted up to 5-fold, identical or different, by cyano,halogen, nitro, carboxyl, hydroxy, trifluoromethyl, trifluoro- methoxy,or by straight-chain or branched alkyl, acyl, hydroxyalkyl, alkylthio,alkoxycarbonyl, oxyalkoxycarbonyl or alkoxy each with up to 7 carbonatoms, or by a group of the formula

—NR_(XI-3)R_(XI-4),

[0509] in which

[0510] R_(XI-3) and R_(XI-4) are identical or different and denotehydrogen, phenyl, or straight-chain or branched alkyl with up to 6carbon atoms

[0511] D_(XI) stands for a radical of the formula

[0512] in which

[0513] R_(XI-5), R_(XI-6) and R_(XI-9), independent of each other,denote cycloalkyl with 3 to 6 carbon atoms, or denote aryl with 6 to 10carbon atoms, or denote a 5- to 7-membered, possibly benzocondensated,saturated or unsaturated, mono-, bi- or tricyclic heterocycle with up to4 heteroatoms of the series S, N and/or O, where the cycles are possiblysubstituted—in the case of the nitrogen-containing rings also via theN-function-up to 5-fold, identical or different, by halogen,trifluoromethyl, nitro, hydroxy, cyano, carboxyl, trifluoromethoxy,straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxyor alkoxycarbonyl with up to 6 carbon atoms each. by aryl ortrifluoromethyl substituted aryl with 6 to 10 carbon atoms each, or by apossibly benzocondensated aromatic 5- to 7-membered heterocycle with upto 3 heteroatoms of the series S, N and/or O, and/or are substituted bya group of the formula

—OR_(XI-10), —SR_(XI-11), —SO₂R_(XI-12) or —NR_(XI-13)R_(XI-14),

[0514] in which

[0515] R_(XI-10), R_(XI-11) and R_(XI-12), independent of each other,denote aryl with 6 to 10 carbon atoms, which itself is substituted up to2-fold, identical or different, by phenyl, halogen. or by straight-chainor branched alkyl with up to 6 carbon atoms,

[0516] R_(XI-13) and R_(XI-14) are identical or different and have themeaning given above for R_(XI-3) and R_(XI-4),

[0517] or

[0518] R_(XI-5) and/or R_(XI-6) denote a radical of the formula

[0519] R_(XI-7) denotes hydrogen, halogen or methyl,

[0520] and

[0521] R_(XI-8) denotes hydrogen, halogen, azido, trifluoromethyl,hydroxy, trifluoromethoxy, straight-chain or branched alkoxy or alkylwith up to 6 carbon atoms each, or a radical of the formula—NR_(XI-15)R_(XI-6),

[0522] in which

[0523] R_(XI-15) and R_(XI-16) are identical or different and have themeaning given above for R_(XI-3) and R_(XI-4).

[0524] or

[0525] R_(XI-7) and R_(XI-8) together form a radical of the formula ═Oor ═NR_(XI-17), in which

[0526] R_(XI-17) denotes hydrogen or straight-chain or branched alkyl,alkoxy or acyl with up to 6 carbon atoms each,

[0527] L_(XI) denotes a straight-chain or branched alkylene- oralkenylene chain with up to 8 carbon atoms each, which is possiblysubstituted up to 2-fold by hydroxy,

[0528] T_(XI) and X_(XI) are identical or different and denote astraight-chain or branched alkylene chain with up to 8 carbon atoms,

[0529] or

[0530] T_(XI) and X_(XI) denotes a bond,

[0531] V_(XI) stands for an oxygen- or sulfur atom or for an —NR_(XI-18)group,

[0532] in which

[0533] R_(XI-18) denotes hydrogen or straight-chain or branched alkylwith up to 6 carbon atoms, or phenyl,

[0534] E_(XI) stands for cycloalkyl with 3 to 8 carbon atoms, or standsfor straight-chain or branched alkyl with up to 8 carbon atoms, which ispossibly substituted by cycloalkyl with 3 to 8 carbon atoms or hydroxy,or stands for phenyl, which is possibly substituted by halogen ortrifluoromethyl,

[0535] R_(XI-1) and R_(XI-2) together form a straight-chain or branchedalkylene chain with up to 7 carbon atoms, which must be substituted by acarbonyl group and/or by a radical of the formula

[0536] in which

[0537] a and b are identical or different and denote a number 1, 2 or 3

[0538] R_(XI-19) denotes hydrogen, cycloalkyl with 3 to 7 carbon atoms,straight-chain or branched silylalkyl with up to 8 carbon atoms, orstraight-chain or branched alkyl with up to 8 carbon atoms, which ispossibly substituted by hydroxy, straight-chain or branched alkoxy withup to 6 carbon atoms, or by phenyl, which itself can be substituted byhalogen, nitro, trifluoromethyl, trifluoromethoxy or by phenylsubstituted by phenyl or tetrazol, and alkyl is possibly substituted bya group of the formula

—OR_(XI-22),

[0539] in which

[0540] R_(XI-22) denotes straight-chain or branched acyl with up to 4carbon atoms, or benzyl,

[0541] or

[0542] R_(XI-19) denotes straight-chain or branched acyl with up to 20carbon atoms or benzoyl, which is possibly substituted by halogen,trifluoromethyl, nitro or trifluoromethoxy, or denotes straight-chain orbranched fluoroacyl with up to 8 carbon atoms and 9 fluorine atoms,

[0543] R_(XI-20) and R_(XI-21) are identical or different, denotinghydrogen, phenyl or straight-chain or branched alkyl with up to 6 carbonatoms,

[0544] or

[0545] R_(XI-20) and R_(XI-21) together form a 3- to 6-memberedcarbocycle, and, possibly also geminally, the alkylene chain formed byR_(XI-1)and R_(XI-2), is possibly substituted up to 6-fold, identical ordifferent, by trifluoromethyl, hydroxy, nitrile, halogen, carboxyl,nitro, azido, cyano, cycloalkyl or cycloalkyloxy with 3 to 7 carbonatoms each, by straight-chain or branched alkoxycarbonyl, alkoxy oralkoxythio with up to 6 carbon atoms each, or by straight-chain orbranched alkyl with up to 6 carbon atoms, which itself is substituted upto 2-fold, identical or different, by hydroxyl, benzyloxy,trifluoromethyl, benzoyl, straight-chain or branched alkoxy, oxyacyl orcarboxyl with up to 4 carbon atoms each, and/or phenyl—which itself canbe substituted by halogen, trifluoromethyl or trifluoromethoxy, and/orthe alkylene chain formed by R_(XI-1) and R_(XI-2) is substituted, alsogeminally, possibly up to 5-fold, identical or different, by phenyl,benzoyl, thiophenyl or sulfobenzyl—which themselves are possiblysubstituted by halogen, trifluoromethyl, trifluoromethoxy or nitro,and/or the alkylene chain formed by R_(XI-1) and R_(XI-2) is possiblysubstituted by a radical of the formula

[0546] in which

[0547] c denotes a number 1, 2, 3 or 4,

[0548] d denotes a number 0 or 1,

[0549] R_(XI-23) and R_(XI-24) are identical or different and denotehydrogen, cycloalkyl with 3 to 6 carbon atoms, straight-chain orbranched alkyl with up to 6 carbon atoms, benzyl or phenyl, which ispossibly substituted up to 2-fold. identical or different, by halogen,trifluoromethyl, cyano, phenyl or nitro, and/or the alkylene chainformed by R_(XI-1) and R_(XI-2) is possibly substituted by aspiro-jointed radical of the formula

[0550] in which

[0551] W_(XI) denotes either an oxygen or a sulfur atom,

[0552] Y_(XI) and Y′_(XI) together form a 2- to 6-memberedstraight-chain or branched alkylene chain,

[0553] e is a number 1, 2, 3, 4, 5, 6 or 7,

[0554] f denotes a number 1 or 2,

[0555] R_(XI-25), R_(XI-26), R_(XI-27), R_(XI-28), R_(XI-29), R_(XI-30)and R_(XI-31) are identical or different and denote hydrogen,trifluoromethyl, phenyl, halogen, or straight-chain or branched alkyl oralkoxy with up to 6 carbon atoms each,

[0556] or

[0557] R_(XI-25) and R_(XI-26) or R_(XI-27) and R_(XI-28) together forma straight-chain or branched alkyl chain with up to 6 carbon atoms,

[0558] or

[0559] R_(XI-25) and R_(XI-26) or R_(XI-27) and R_(XI-28) together forma radical of the formula

[0560] in which

[0561] W_(XI) has the meaning given above,

[0562] g is a number 1, 2, 3, 4, 5, 6 or 7,

[0563] R_(XI-32) and R_(XI-33) together form a 3- to 7-memberedheterocycle that contains an oxygen- or sulfur atom or a group of theformula SO, SO₂ or —NR_(XI-34),

[0564] in which R_(XI-34) denotes hydrogen, phenyl, benzyl, orstraight-chain or branched alkyl with up to 4 carbon atoms.

[0565] Compounds of Formula XI are disclosed in WO 9914174, the completedisclosure of which is incorporated by reference.

[0566] Another class of CETP inhibitors that finds utility with thepresent invention consists of 2-aryl-substituted pyridines having theFormula XII

[0567] and pharmaceutically acceptable forms thereof, in which

[0568] A_(XII) and E_(XII) are identical or different and stand for arylwith 6 to 10 carbon atoms which is possibly substituted, up to 5-foldidentical or different, by halogen, hydroxy, trifluoromethyl,trifluoromethoxy, nitro or by straight-chain or branched alkyl, acyl,hydroxy alkyl or alkoxy with up to 7 carbon atoms each, or by a group ofthe formula —NR_(XII-1)R_(XI-2),

[0569] where

[0570] R_(XII-1) and R_(XII-2) are identical or different and are meantto be hydrogen, phenyl or straight-chain or branched alkyl with up to 6carbon atoms,

[0571] D_(XII) stands for straight-chain or branched alkyl with up to 8carbon atoms, which is substituted by hydroxy,

[0572] L_(XII) stands for cycloalkyl with 3 to 8 carbon atoms or forstraight-chain or branched alkyl with up to 8 carbon atoms, which ispossibly substituted by cycloalkyl with 3 to 8 carbon atoms, or byhydroxy,

[0573] T_(XII) stands for a radical of the formula R_(XII-3)-X_(XII)- or

[0574] where

[0575] R_(XII-3) and R_(XII-4) are identical or different and are meantto be cycloalkyl with 3 to 8 carbon atoms, or aryl with 6 to 10 carbonatoms, or a 5- to 7-membered aromatic, possibly benzocondensatedheterocycle with up to 3 heteroatoms from the series S, N and/or O,which are possibly substituted up to 3-fold identical or different, bytrifluoromethyl, trifluoromethoxy, halogen, hydroxy, carboxyl, nitro, bystraight-chain or branched alkyl, acyl, alkoxy or alkoxycarbonyl with upto 6 carbon atoms each or by phenyl, phenoxy or phenylthio which in turncan be substituted by halogen trifluoromethyl or trifluoromethoxy,and/or where the cycles are possibly substituted by a group of theformula

—NR_(XII-7)R_(XII-8),

[0576] where

[0577] R_(XII-7) and R_(XII-8) are identical or different and have themeaning of R_(XII-1) and R_(XII-2) given above,

[0578] X_(XII) is a straight-chain or branched alkyl or alkenyl with 2to 10 carbon atoms each, possibly substituted up to 2-fold by hydroxy orhalogen,

[0579] R_(XII-5) stands for hydrogen,

[0580] and

[0581] R_(XII-6) means to be hydrogen, halogen, mercapto, azido,trifluoromethyl, hydroxy, trifluoromethoxy, straight-chain or branchedalkoxy with up to 5 carbon atoms, or a radical of the formula

—NR_(XII-9)R_(XII-10),

[0582] where

[0583] R_(XII-9) and R_(XI-10) are identical or different and have themeaning of R_(XII-1) and R_(XII-22) given above,

[0584] or

[0585] R_(XII-5) and R_(XII-6), together with the carbon atom, form acarbonyl group.

[0586] Compounds of Formula XII are disclosed in EP 796846-A1, thecomplete disclosure of which is incorporated by reference.

[0587] In a preferred embodiment, the CETP inhibitor is selected fromthe following compounds of Formula XII:

[0588]4,6-bis-(p-fluorophenyl)-2-isopropyl-3-[(p-trifluoromethylphenyl)-(fluoro)-methyl]-5-(1-hydroxyethyl)pyridine;

[0589]2,4-bis-(4-fluorophenyl)-6-isopropyl-5-[4-(trifluoromethylphenyl)-fluoromethyl]-3-hydroxymethyl)pyridine;and

[0590]2,4-bis-(4-fluorophenyl)-6-isopropyl-5-[2-(3-trifluoromethylphenyl)vinyl]-3-hydroxymethyl)pyridine.

[0591] Another class of CETP inhibitors that finds utility with thepresent invention consists of compounds having the Formula XIII

[0592] and pharmaceutically acceptable forms thereof, in which

[0593] R_(XIII) is a straight chain or branched C₁-C₁₀ alkyl; straightchain or branched C₂-C₁₀ alkenyl; halogenated C₁-C₄ lower alkyl; C₃-C₁₀cycloalkyl that may be substituted; C₅₋₈ cycloalkenyl that may besubstituted; C₃-C₁₀ cycloalkyl C₁₋₁₀ alkyl that may be substituted; arylthat may be substituted; aralkyl that may be substituted; or a 5- or6-membered heterocyclic group having 1 to 3 nitrogen atoms, oxygen atomsor sulfur atoms that may be substituted,

[0594] X_(XIII-1), X_(XIII-2), X_(XIII-3), X_(XIII-4) may be the same ordifferent and are a hydrogen atom; halogen atom; C₁₋₄ lower alkyl;halogenated C₁₋₄ lower alkyl; C₁₋₄ lower alkoxy; cyano group; nitrogroup; acyl; or aryl, respectively;

[0595] Y_(XIII) is —CO—; or —SO₂—; and

[0596] Z_(XIII) is a hydrogen atom; or mercapto protective group.

[0597] Compounds of Formula XIII are disclosed in WO 98/35937, thecomplete disclosure of which is incorporated by reference.

[0598] In a preferred embodiment, the CETP inhibitor is selected fromthe following compounds of Formula XIII:

[0599] N,N′-(dithiodi-2,1-phenylene)bis[2,2-dimethyl-propanamide];

[0600]N,N′-(dithiodi-2,1-phenylene)bis[1-methyl-cyclohexanecarboxamide];

[0601]N,N′-(dithiodi-2,1-phenylene)bis[1-(3-methylbutyl)-cyclopentanecarboxamide];

[0602]N,N′-(dithiodi-2,1-phenylene)bis[1-(3-methylbutyl)-cyclohexanecarboxamide];

[0603]N,N′-(dithiodi-2,1-phenylene)bis[1-(2-ethylbutyl)-cyclohexanecarboxamide];

[0604]N,N′-(dithiodi-2,1-phenylene)bis-tricyclo[3.3.1.1^(3,7)]decane-1-carboxamide;

[0605] propanethioic acid,2-methyl-,S-[2[[[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino]phenyl]ester;

[0606] propanethioic acid, 2,2-dimethyl-,S-[2-[[[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino]phenyl] ester; and

[0607] ethanethioic acid,S-[2-[[[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino]phenyl] ester.

[0608] Another class of CETP inhibitors that finds utility with thepresent invention consists of polycyclic aryl and heteroaryltertiary-heteroalkylamines having the Formula XIV

[0609] and pharmaceutically acceptable forms thereof, wherein:

[0610] n_(XIV) is an integer selected from 0 through 5;

[0611] R_(XIV-1) is selected from the group consisting of haloalkyl,haloalkenyl, haloalkoxyalkyl, and haloalkenyloxyalkyl;

[0612] X_(XIV) is selected from the group consisting of O, H, F, S,S(O),NH, N(OH), N(alkyl), and N(alkoxy);

[0613] R_(XIV-16) is selected from the group consisting of hydrido,alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl,alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, aralkoxyalkyl,heteroaralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl,haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl,haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl,halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl,perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, monocarboalkoxyalkyl,monocarboalkoxy, dicarboalkoxyalkyl, monocarboxamido, monocyanoalkyl,dicyanoalkyl, carboalkoxycyanoalkyl, acyl, aroyl, heteroaroyl,heteroaryloxyalkyl, dialkoxyphosphonoalkyl, trialkylsilyl, and a spacerselected from the group consisting of a covalent single bond and alinear spacer moiety having from 1 through 4 contiguous atoms linked tothe point of bonding of an aromatic substituent selected from the groupconsisting of R_(XIV-4), R_(XIV-8), R_(XIV-9), and R_(XIV-13) to form aheterocyclyl ring having from 5 through 10 contiguous members with theprovisos that said spacer moiety is other than a covalent single bondwhen R_(XIV-2) is alkyl and there is no R_(XIV-16) wherein X is H or F;

[0614] D_(XIV-1) D_(XIV-2), J_(XIV-1), J_(XIV-2) and K_(XIV-1) areindependently selected from the group consisting of C, N, O, S and acovalent bond with the provisos that no more than one of D_(XIV-1),D_(XIV-2), J_(XIV-1), J_(XIV-2) and K_(XIV-1) is a covalent bond, nomore than one of D_(XIV-1), D_(XIV-2), J_(XIV-1), J_(XIV-2) andK_(XIV-1) is O, no more than one of D_(XIV-1), D_(XIV-2), J_(XIV-1),J_(XIV-2) and K_(XIV-1) is S, one of D_(XIV-1), D_(XIV-2), J_(XIV-1),J_(XIV-2) and K_(XIV-1) must be a covalent bond when two of D_(XIV-1),D_(XIV-2) J_(XIV-1), J_(XIV-2) and K_(XIV-1) are O and S, and no morethan four of D_(XIV-1), D_(XIV-2), J_(XIV-1), J_(XIV-2) and K_(XIV-1)are N;

[0615] D_(XIV-3), D_(XIV-4), J_(XIV-3), J_(XIV-4) and K_(XIV-2) areindependently selected from the group consisting of C, N, O, S and acovalent bond with the provisos that no more than one of D_(XIV- 3),D_(XIV-4), J_(XIV-3), J_(XIV-4) and K_(XIV-2) is a covalent bond, nomore than one of D_(XIV-3), D_(XIV-4), J_(XIV- 3), J_(XIV-4) andK_(XIV-2) is O, no more than one of D_(XIV-3), D_(XIV-4), J_(XIV-3),J_(XIV-4) and K_(XIV-2) is S, one of D_(XIV-3), D_(XIV-4), J_(XIV-3),J_(XIV-4) and K_(XIV-2) must be a covalent bond when two of D_(XIV-3),D_(XIV-4), J_(XIV-3), J_(XIV-4) and K_(XIV-2) are O and S, and no morethan four of D_(XIV-3), D_(XIV-4), J_(XIV-3), J_(XIV-4) and K_(XIV-2)and K_(XIV-2) are N;

[0616] R_(XIV-2) is independently selected from the group consisting ofhydrido, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylamino,dialkylamino, alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkoxyalkyl,aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl,alkylthioalkyl, aralkylthioalkyl, arylthioalkyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl,haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy,aloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl,perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl,heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl,dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl,alkylsulfinyl, alkylsulfonyl, alkylsulfinylalkyl, alkylsulfonylalkyl,haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl,arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl,cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl,cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl,heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl,aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide,carboxamidoalkyl, carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono,dialkoxyphosphonoalkyl, and diaralkoxyphosphonoalkyl;

[0617] R_(XIV-2) and R_(XIV-3) are taken together to form a linearspacer moiety selected from the group consisting of a covalent singlebond and a moiety having from 1 through 6 contiguous atoms to form aring selected from the group consisting of a cycloalkyl having from 3through 8 contiguous members, a cycloalkenyl having from 5 through 8contiguous members, and a heterocyclyl having from 4 through 8contiguous members;

[0618] R_(XIV-3) is selected from the group consisting of hydrido,hydroxy, halo, cyano, aryloxy, hydroxyalkyl, amino, alkylamino,dialkylamino, acyl, sulfhydryl, acylamido, alkoxy, alkylthio, arylthio,alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl,heteroarylthio, aralkylthio, aralkoxyalkyl, alkylsulfinylalkyl,alkylsulfonylalkyl, aroyl, heteroaroyl, aralkylthioalkyl,heteroaralkylthioalkyl, heteroaryloxyalkyl, alkenyloxyalkyl,alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl,haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy,haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl,perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl,heteroarylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl,monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl,alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl,arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl,aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl,cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl,carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl,carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono,dialkoxyphosphonoalkyl, and diaralkoxyphosphonoalkyl;

[0619] Y_(XIV) is selected from a group consisting of a covalent singlebond,(C(R_(XIV-14))₂)_(qXIV) wherein _(qXIV) is an integer selected from1 and 2 and (CH(R_(XIV-14)))_(gXIV)-W_(XIV)-(CH(R_(XIV-14))) _(pXIV)wherein _(gXlV) and _(pXIV) are integers independently selected from 0and 1;

[0620] R_(XIV-14) is independently selected from the group consisting ofhydrido, hydroxy, halo, cyano, aryloxy, amino, alkylamino, dialkylamino,hydroxyalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, sulfhydryl,acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl,aralkyl, aryloxyalkyl, aralkoxyalkylalkoxy, alkylsulfinylalkyl,alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl,alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl,arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl,cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl,halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl,perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl,heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl,monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl,haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl,arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl,cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl,carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl,carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono,dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected froma moiety having a chain length of 3 to 6 atoms connected to the point ofbonding selected from the group consisting of R_(XIV-9) and R_(XIV-13)to form a ring selected from the group consisting of a cycloalkenyl ringhaving from 5 through 8 contiguous members and a heterocyclyl ringhaving from 5 through 8 contiguous members and a spacer selected from amoiety having a chain length of 2 to 5 atoms connected to the point ofbonding selected from the group consisting of R_(XIV-4) and R_(XIV-8) toform a heterocyclyl having from 5 through 8 contiguous members with theproviso that, when Y_(XIV) is a covalent bond, an R_(XIV-14) substituentis not attached to Y_(XIV);

[0621] R_(XIV-14) and R_(XIV-14), when bonded to the different atoms,are taken together to form a group selected from the group consisting ofa covalent bond, alkylene, haloalkylene, and a spacer selected from agroup consisting of a moiety having a chain length of 2 to 5 atomsconnected to form a ring selected from the group of a saturatedcycloalkyl having from 5 through 8 contiguous members, a cycloalkenylhaving from 5 through 8 contiguous members, and a heterocyclyl havingfrom 5 through 8 contiguous members;

[0622] R_(XIV-14) and R_(XIV-14), when bonded to the same atom are takentogether to form a group selected from the group consisting of oxo,thiono, alkylene, haloalkylene, and a spacer selected from the groupconsisting of a moiety having a chain length of 3 to 7 atoms connectedto form a ring selected from the group consisting of a cycloalkyl havingfrom 4 through 8 contiguous members, a cycloalkenyl having from 4through 8 contiguous members, and a heterocyclyl having from 4 through 8contiguous members;

[0623] W_(XIV) is selected from the group consisting of O, C(O), C(S),C(O)N(R_(XIV-14)), C(S)N(R_(XIV-14)), (R_(XIV-14))NC(O),(R_(XIV-14))NC(S), S, S(O), S(O)₂, S(O)₂N(R_(XIV-14)),(R_(XIV-14))NS(O)₂, and N(R_(XIV-14)) with the proviso that R_(XIV-14)is selected from other than halo and cyano;

[0624] Z_(XIV) is independently selected from a group consisting of acovalent single bond, (C(R_(XIV-15))₂)_(qXIV-2) wherein _(qXIV-2) is aninteger selected from 1 and 2,(CH(R_(XIV-15)))_(jXIV)-W-(CH(R_(XIV-15)))_(kXIV) wherein _(jXIV) and_(kXIV) are integers independently selected from 0 and 1 with theproviso that, when Z_(XIV) is a covalent single bond, an R_(XIV-15)substituent is not attached to Z_(XIV);

[0625] R_(XIV-15) is independently selected, when Z_(XIV) is(C(R_(XIV-15))₂)_(qXIV) wherein _(qXIV) is an integer selected from 1and 2, from the group consisting of hydrido, hydroxy, halo, cyano,aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, acyl, aroyl,heteroaroyl, heteroaryloxyalkyl, sulfhydryl, acylamido, alkoxy,alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl,aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl,aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl,heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl,cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl,cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl,halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl,perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl,heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl,monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl,haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl,arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl,cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl,carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl,carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono,dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected froma moiety having a chain length of 3 to 6 atoms connected to the point ofbonding selected from the group consisting of R_(XIV-4) and R_(XIV-8) toform a ring selected from the group consisting of a cycloalkenyl ringhaving from 5 through 8 contiguous members and a heterocyclyl ringhaving from 5 through 8 contiguous members, and a spacer selected from amoiety having a chain length of 2 to 5 atoms connected to the point ofbonding selected from the group consisting of R_(XIV-9) and R_(XIV-13)to form a heterocyclyl having from 5 through 8 contiguous members;

[0626] R_(XIV-15) and R_(XIV-15), when bonded to the different atoms,are taken together to form a group selected from the group consisting ofa covalent bond, alkylene, haloalkylene, and a spacer selected from agroup consisting of a moiety having a chain length of 2 to 5 atomsconnected to form a ring selected from the group of a saturatedcycloalkyl having from 5 through 8 contiguous members, a cycloalkenylhaving from 5 through 8 contiguous members, and a heterocyclyl havingfrom 5 through 8 contiguous members;

[0627] R_(XIV-15) and R_(XIV-15), when bonded to the same atom are takentogether to form a group selected from the group consisting of oxo,thiono, alkylene, haloalkylene, and a spacer selected from the groupconsisting of a moiety having a chain length of 3 to 7 atoms connectedto form a ring selected from the group consisting of a cycloalkyl havingfrom 4 through 8 contiguous members, a cycloalkenyl having from 4through 8 contiguous members, and a heterocyclyl having from 4 through 8contiguous members;

[0628] R_(XIV-15) is independently selected, when Z_(XIV) is(CH(R_(XIV-15)))_(jXIV)-W-(CH(R_(XIV-15)))_(kXIV) wherein _(jXIV) and_(kXIV) are integers independently selected from 0 and 1, from the groupconsisting of hydrido, halo, cyano, aryloxy, carboxyl, acyl, aroyl,heteroaroyl, hydroxyalkyl, heteroaryloxyalkyl, acylamido, alkoxy,alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl,aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, aralkoxyalkyl,heteroaralkoxyalkyl, alkylsulfonylalkyl, alkylsulfinylalkyl,alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl,haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy,haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl,perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl,heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl,dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl,alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl,arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl,aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl,cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl,carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy,dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected froma linear moiety having a chain length of 3 to 6 atoms connected to thepoint of bonding selected from the group consisting of R_(XIV-4) andR_(XIV-8) to form a ring selected from the group consisting of acycloalkenyl ring having from 5 through 8 contiguous members and aheterocyclyl ring having from 5 through 8 contiguous members, and aspacer selected from a linear moiety having a chain length of 2 to 5atoms connected to the point of bonding selected from the groupconsisting of R_(XIV-9) and R_(XIV-13) to form a heterocyclyl ringhaving from 5 through 8 contiguous members;

[0629] R_(XIV-4), R_(XIV-5), R_(XIV-6), R_(XIV-7), R_(XIV-8), R_(XIV-9),R_(XIV-10), R_(XIV-11), R_(XIV-12), and R_(XIV-13) are independentlyselected from the group consisting of perhaloaryloxy, alkanoylalkyl,alkanoylalkoxy, alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy,heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy,alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy,aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido,N-cycloalkylcarboxamido, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl,cyanoalkoxy, heterocyclylcarbonyl, hydrido, carboxy, heteroaralkylthio,heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy,heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl,heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl,aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl,cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl,cycloalkylsulfonylalkyl, heteroarylamino,N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio,alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy,cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy,cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl,hydroxy, amino, thio, nitro, lower alkylamino, alkylthio,alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl,heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl,arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl,heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl,haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido,alkylaminosulfonyl, amidosulfonyl, monoalkyl, amidosulfonyl, dialkylamidosulfonyl, monoarylamidosulfonyl, arylsulfonamido,diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl,arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl,heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl,heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl,alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy,cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl,lower cycloalkenylalkyl, halo, haloalkyl; haloalkenyl, haloalkoxy,hydroxyhaloalkyl, hydroxyaralkyl, hydroxyaikyl, hydoxyheteroaralkyl,haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl,saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl,heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl,carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido,arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl,carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy,phosphono, phosphonoalkyl, diaralkoxyphosphono, anddiaralkoxyphosphonoalkyl with the proviso that there are one to fivenon-hydrido ring substituents R_(XIV-4), R_(XIV-5), R_(XIV-6),R_(XIV-7), and R_(XIV-8) present, that there are one to five non-hydridoring substituents R_(XIV-9), R_(XIV-10), R_(XIV-11), R_(XIV-12), andR_(XIV-13) present, and R_(XIV-4), R_(XIV-5), R_(XIV-6), R_(XIV-7),R_(XIV-8), R_(XIV-9), R_(XIV-10), R_(XIV-11), R_(XIV-12), and R_(XIV-13)are each independently selected to maintain the tetravalent nature ofcarbon, trivalent nature of nitrogen, the divalent nature of sulfur, andthe divalent nature of oxygen;

[0630] R_(XIV-4) and R_(XIV-5), R_(XIV-5) and R_(XIV-6), R_(XIV-6) andR_(XIV-7),R_(XIV-7) and R_(XIV-8), R_(XIV-8) and R_(XIV-9), R_(XIV-9)and R_(XIV-10), R_(XIV-10) and R_(XIV-11), R_(XIV-11) and R_(XIV-12),and R_(XIV-12) and R_(XIV-13) are independently selected to form spacerpairs wherein a spacer pair is taken together to form a linear moietyhaving from 3 through 6 contiguous atoms connecting the points ofbonding of said spacer pair members to form a ring selected from thegroup consisting of a cycloalkenyl ring having 5 through 8 contiguousmembers, a partially saturated heterocyclyl ring having 5 through 8contiguous members, a heteroaryl ring having 5 through 6 contiguousmembers, and an aryl with the provisos that no more than one of thegroup consisting of spacer pairs R_(XIV-4) and R_(XIV-5), R_(XIV-5) andR_(XIV-6), R_(XIV-6) and R_(XIV-7), and R_(XIV-7) and R_(XIV-8) are usedat the same time and that no more than one of the group consisting ofspacer pairs R_(XIV-9) and R_(XIV-10), R_(XIV-10) and R_(XIV-11),R_(XIV-11) and R_(XIV-12), and R_(XIV-12) and R_(XIV-13) are used at thesame time;

[0631] R_(XIV-4) and R_(XIV-9), R_(XIV-4) and R_(XIV-13), R_(XIV-8) andR_(XIV-9), and R_(XIV-8) and R_(XIV-13) are independently selected toform a spacer pair wherein said spacer pair is taken together to form alinear moiety wherein said linear moiety forms a ring selected from thegroup consisting of a partially saturated heterocyclyl ring having from5 through 8 contiguous members and a heteroaryl ring having from 5through 6 contiguous members with the proviso that no more than one ofthe group consisting of spacer pairs R_(XIV-4) and R_(XIV-9), R_(XIV-4)and R_(XIV-13), R_(XIV-8) and R_(XIV-9), and R_(XIV-8) and R_(XIV-13) isused at the same time.

[0632] Compounds of Formula XIV are disclosed in WO 00/18721, the entiredisclosure of which is incorporated by reference.

[0633] In a preferred embodiment, the CETP inhibitor is selected fromthe following compounds of Formula XIV:

[0634]3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0635]3-[[3-(3-isopropylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0636]3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0637]3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]1,1,1-trifluoro-2-propanol;

[0638] 3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0639]3-[[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0640]3-[[3-(4-methlylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0641]3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0642]3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0643] 3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0644]3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0645]3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0646] 3-[[3-(3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0647]3-[[3-(3-t-butylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]1,1,1-trifluoro-2-propanol;

[0648]3-[[3-(3-methylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0649]3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0650]3-[[3-(phenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-30trifluoro-2-propanol;

[0651]3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0652] 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethoxy)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0653]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethyl)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0654]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0655]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethylthio)-phenyl]methoxy]phenyl]amino]-1,1,1,-trifluoro-2-propanol;

[0656]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0657]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0658]3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0659]3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0660]3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0661]3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0662]3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1,-trifluoro-2-propanol;

[0663]3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(pentafluoroethymethyl]amino]-1,1,1-trifluoro-2-propanol;

[0664] 3-[[3-(3-isopropylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0665] 3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0666] 3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0667] 3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0668] 3-[[3-(4-fluorophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0669] 3-[[3-(4-methylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0670] 3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0671] 3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0672]3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(pentafluoroethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0673]3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0674] 3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0675] 3-[[3-(3-ethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0676] 3-[[3-(3-t-butylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0677] 3-[[3-(3-methylphenoxy)phenyl][[3-pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0678]3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0679] 3-[[3-(phenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0680]3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0681]3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0682]3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethyl)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0683]3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0684]3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0685]3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3,5-difluorophenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0686]3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[cyclohexylmethoxy]phenyl]-amino]-1,1,1-trifluoro-2-propanol;

[0687]3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0688]3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0689] 3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0690]3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0691]3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(pentafluoroethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0692]3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0693] 3-[[3-(3-isopropylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0694] 3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0695] 3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0696] 3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0697] 3-[[3-(4-fluorophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0698] 3-[[3-(4-methylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0699] 3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifiuoro-2-propanol;

[0700] 3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0701]3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(heptafluoropropyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0702]3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0703] 3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0704] 3-[[3-(3-ethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0705] 3-[[3-(3-t-butylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0706] 3-[[3-(3-methylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0707]3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0708] 3-[[³-(phenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0709]3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0710]3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0711]3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethyl)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0712]3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3,5-dimethylphenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0713]3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethylthio)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0714]3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3,5-difluorophenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0715]3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[cyclohexylmethoxy]phenyl]-amino]-1,1,1-trifluoro-2-propanol;

[0716]3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0717]3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0718] 3-[[³-(³-difluoromethoxyphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0719]3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0720]3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(heptafluoropropyl)-phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0721]3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0722]3-[[3-(3-isopropylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0723]3-[[3-(3-cyclopropylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0724]3-[[3-(3-(2-furyl)phenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0725]3-[[3-(2,3-dichlorophenoxy)phenyl][[2-fluoro-5-(trifiuoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0726]3-[[3-(4-fluorophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0727]3-[[3-(4-methylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0728]3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0729]3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0730]3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[2-fluoro-5-(trifluoro-20methyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0731]3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0732]3-[[3-(3,5-dimethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0733] 3-[[3-(3-ethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0734] 3-[[3-(3-t-butylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-l 1,1,1-trifluoro-2-propanol;

[0735] 3-[[3-(3-methylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-30 amino]-1,1,1-trifluoro-2-propanol;

[0736]3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0737] 3-[[3-(phenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0738]3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0739]3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0740]3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethyl)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0741]3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0742]3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0743]3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0744]3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0745]3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0746]3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0747]3-[[3-(3-difluoromethoxyphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0748]3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0749]3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0750]3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0751]3-[[3-(3-isopropylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0752]3-[[3-(3-cyclopropylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-30methyl]amino]-1,1,1-trifluoro-2-propanol;

[0753]3-[[3-(3-(2-furyl)phenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0754]3-[[3-(2,3-dichlorophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0755] 3-[[3-(4-fluorophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0756] 3-[[3-(4-methylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0757]3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0758]3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0759]3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[2-fluoro-4-(trifluoro-methyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0760]3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0761]3-[[3-(3,5-dimethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0762] 3-[[3-(3-ethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0763] 3-[[3-(3-t-butylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0764] 3-[[3-(3-methylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0765]3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0766] 3-[[3-(phenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0767]3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0768]3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0769]3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethyl)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0770]3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0771]3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0772]3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0773]3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0774]3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0775]3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0776]3-[[3-(3-difluoromethoxyphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0777]3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;and

[0778]3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[2-fluoro-4-(trifluoro-methyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol.

[0779] Another class of CETP inhibitors that finds utility with thepresent invention consists of substitued N-Aliphatic-N-Aromatictertiary-Heteroalkylamines having the Formula XV

[0780] and pharmaceutically acceptable forms thereof, wherein:

[0781] n_(XV) is an integer selected from 1 through 2;

[0782] A_(XV) and Q_(XV) are independently selected from the groupconsisting of—CH₂(CR_(XV-37)R_(XV-38))_(vXV)-(CR_(XV-33)R_(XV-34))_(uXV)-T_(XV)-(CR_(XV-35)R_(XV-36))_(wXV)-H,

[0783] with the provisos that one of A_(XV) and Q_(XV) must be AQ-1 andthat one of A_(XV) and Q_(XV) must be selected from the group consistingof AQ-2 and—C₂(CR_(XV-37)R_(XV-38))_(vXV)-(CR_(XV-33)R_(XV-34))_(uXV)-T_(XV)-(CR_(XV-35)R_(XV-36))_(wXV)-H;

[0784] T_(XV) is selected from the group consisting of a single covalentbond, O, S, S(O), S(O)₂, C(R_(XV-33))═C(R_(XV-35)), and

[0785] C≡C;

[0786]_(vXV) is an integer selected from 0 through 1 with the provisothat _(vXV) is 1 when any one of R_(XV-33), R_(XV-34), R_(XV-35), andR_(XV-36) is aryl or heteroaryl;

[0787]_(uXV) and _(wXV) are integers independently selected from 0through 6;

[0788] A_(XV-1) is C(R_(XV-30));

[0789] D_(XV-1), D_(XV-2), J_(XV-1), J_(XV-2), and K_(XV-1) areindependently selected from the group consisting of C, N, O, S and acovalent bond with the provisos that no more than one of D_(XV-1),D_(XV-2), J_(XV-1), J_(XV-2), and K_(XV-1) is a covalent bond, no morethan one of D_(XV-1), D_(XV-2), J_(XV-1), J_(XV-2), and K_(XV-1), isO,no more than one of D_(XV-1), D_(XV-2), J_(XV-1), J_(XV-2), andK_(XV-1) is S, one of D_(XV-1), D_(XV-2), J_(XV-1), J_(XV-2), andK_(XV-1) must be a covalent bond when two of D_(XV-1), D_(XV-2),J_(XV-1), J_(XV-2), and K_(XV-1) are O and S, and no more than four ofD_(XV-1), D_(XV-2), J_(XV-1), J_(XV-2), and K_(XV-1) are N;

[0790] B_(XV-1), B_(XV-2), D_(XV-3), D_(XV-4), J_(XV-3), J_(XV-4), andK_(XV-2) are independently selected from the group consisting of C,C(R_(XV-30)), N, O, S and a covalent bond with the provisos that no morethan 5 of B_(XV-1), B_(XV-2), D_(XV-3), J_(XV-4), J_(XV-3), J_(XV-4),and K_(XV-2) are a covalent bond, no more than two of B_(XV-1),B_(XV-2), D_(XV-3), D_(XV-4), J_(XV-3), J_(XV-4), and K_(XV-2) are O, nomore than two of B_(XV-1), B_(XV-2), D_(XV-3), D_(XV-4), J_(XV-3),J_(XV-4), and K_(XV-2) are S, no more than two of B_(XV-1), B_(XV-2),D_(XV-3), D_(XV-4), J_(XV-3), J_(XV-4), and K_(XV-2) are simultaneouslyO, and S, and no more than two of B_(XV-1), B_(XV-2), D_(XV-3),D_(XV-4), J_(XV-3), J_(XV-4), and K_(XV-2) are N;

[0791] B_(XV-1) and D_(XV-3), D_(XV-3) and J_(XV-3), J_(XV-3) andK_(XV-2), K_(XV-2) and J_(XV-4), J_(XV-4) and D_(XV-4), and D_(XV-4) andB_(XV-2) are independently selected to form an in-ring spacer pairwherein said spacer pair is selected from the group consisting ofC(R_(XV-33))═C(R_(XV-35)) and N═N with the provisos that AQ-2 must be aring of at least five contiguous members, that no more than two of thegroup of said spacer pairs are simultaneously

[0792] C(R_(XV-33))═C(R_(XV-35)) and that no more than one of the groupof said spacer pairs can be N═N unless the other spacer pairs are otherthan C(R_(XV-33))═C(R_(XV-35)), O, N, and S;

[0793] R_(XV-1) is selected from the group consisting of haloalkyl andhaloalkoxymethyl;

[0794] R_(XV-2) is selected from the group consisting of hydrido, aryl,alkyl, alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl,perhaloaralkyl, perhaloaryloxyalkyl and heteroaryl;

[0795] R_(XV-3) is selected from the group consisting of hydrido, aryl,alkyl, alkenyl, haloalkyl, and haloalkoxyalkyl;

[0796] Y_(XV) is selected from the group consisting of a covalent singlebond, (CH₂)_(q) wherein q is an integer selected from 1 through 2 and(CH₂)_(j)—O—(CH₂)_(k) wherein j and k are integers independentlyselected from 0 through 1;

[0797] Z_(XV) is selected from the group consisting of covalent singlebond, (CH₂)_(q) wherein q is an integer selected from 1 through 2, and(CH₂)_(j)—O—(CH₂)_(k) wherein j and k are integers independentlyselected from 0 through 1;

[0798] R_(XV-4), R_(XV-8), R_(XV-9) and R_(XV-13) are independentlyselected from the group consisting of hydrido, halo, haloalkyl, andalkyl;

[0799] R_(XV-30) is selected from the group consisting of hydrido,alkoxy, alkoxyalkyl, halo, haloalkyl, alkylamino, alkylthio,alkylthioalkyl, alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl with theproviso that R_(XV-30) is selected to maintain the tetravalent nature ofcarbon, trivalent nature of nitrogen, the divalent nature of sulfur, andthe divalent nature of oxygen;

[0800] R_(XV-30), when bonded to A_(XV-1), is taken together to form anintra-ring linear spacer connecting the A_(XV-1)-carbon at the point ofattachment of R_(XV-30) to the point of bonding of a group selected fromthe group consisting of R_(XV-10), R_(XV-11), R_(XV-12), R_(XV-3), andR_(XV-32) wherein said intra-ring linear spacer is selected from thegroup consisting of a covalent single bond and a spacer moiety havingfrom 1 through 6 contiguous atoms to form a ring selected from the groupconsisting of a cycloalkyl having from 3 through 10 contiguous members,a cycloalkenyl having from 5 through 10 contiguous members, and aheterocyclyl having from 5 through 10 contiguous members;

[0801] R_(XV-30), when bonded to A_(XV-1), is taken together to form anintra-ring branched spacer connecting the A_(XV-1)-carbon at the pointof attachment of R_(XV-30) to the points of bonding of each member ofany one of substituent pairs selected from the group consisting ofsubsitituent pairs R_(XV-10) and R_(XV-11), R_(XV-10) and R_(XV-31),R_(XV-10) and R_(XV-32), R_(XV-10) and R_(XV-12), R_(XV-11) andR_(XV-31), R_(XV-11) and R_(XV-32), R_(XV-11) and R_(XV-12), R_(XV-31)and R_(XV-32), R_(XV-31) and R_(XV-12), and R_(XV-32) and R_(XV-12) andwherein said intra-ring branched spacer is selected to form two ringsselected from the group consisting of cycloalkyl having from 3 through10 contiguous members, cycloalkenyl having from 5 through 10 contiguousmembers, and heterocyclyl having from 5 through 10 contiguous members;

[0802] R_(XV-4), R_(XV-5), R₋₆, R_(XV-7), R_(XV-8), R_(XV-9), R_(XV-10),R_(XV-11), R_(XV-12), R_(XV-13), R_(XV-31), R_(XV-32), R_(XV-33),R_(XV-34), R_(XV-35), and R_(XV-36) are independently selected from thegroup consisting of hydrido, carboxy, heteroaralkylthio, heteroaralkoxy,cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy,aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl,perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl,aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl,cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl,cycloalkylsulfonylalkyl, heteroarylamino,N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio,alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy,cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy,cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl,hydroxy, amino, thio, nitro, lower alkylamino, alkylthio,alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl,heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl,arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl,heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl,haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido,alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkylamidosulfonyl, monoarylamidosulfonyl, arylsulfonamido,diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl,arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl,heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl,heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl,alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy,cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl,lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy,hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl,haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl,saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl,heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl,carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido,alkylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl,carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy,phosphono, phosphonoalkyl, diaralkoxyphosphono, anddiaralkoxyphosphonoalkyl with the provisos that R_(XV-4), R_(XV-5),R_(XV-6), R_(XV-7), R_(XV-8), R_(XV-9), R_(XV-10), R_(XV-11), R_(XV-12),R_(XV-13), R_(XV-31), R_(XV-32), R_(XV-33), R_(XV-34), R_(XV-35), andR_(XV-36) are each independently selected to maintain the tetravalentnature of carbon, trivalent nature of nitrogen, the divalent nature ofsulfur, and the divalent nature of oxygen, that no more than three ofthe R_(XV-33) and R_(XV-34) substituents are simultaneously selectedfrom other than the group consisting of hydrido and halo, and that nomore than three of the R_(XV-35) and R_(XV-36) substituents aresimultaneously selected from other than the group consisting of hydridoand halo;

[0803] R_(XV-9), R_(XV-10), R_(XV-11), R_(XV-12), R_(XV-13), R_(XV-31),and R_(XV-32) are independently selected to be oxo with the provisosthat B_(XV-1), B_(XV-2), D_(XV-3), D_(XV-4), J_(XV-3), J_(XV-4), andK_(XV-2) are independently selected from the group consisting of C andS, no more than two of R_(XV-9), R_(XV-10), R_(XV-11), R_(XV-12),R_(XV-13), R_(XV-31), and R_(XV-32) are simultaneously oxo, and thatR_(XV-9), R_(XV-10), R_(XV-11), R_(XV-12), R_(XV-13), R_(XV-31), andR_(XV-32) are each independently selected to maintain the tetravalentnature of carbon, trivalent nature of nitrogen, the divalent nature ofsulfur, and the divalent nature of oxygen;

[0804] R_(XV-4) and R_(XV-5), R_(XV-5) and R_(XV-6), R_(XV-6) andR_(XV-7), R_(XV-7) and R_(XV-8), R_(XV-9) and R_(XV-10), R_(XV-10) andR_(XV-11), R_(XV-11) and R_(XV-31), R_(XV-31) and R_(XV-32), R_(XV-32)and R_(XV-12), and R_(XV-12) and R_(XV-13) are independently selected toform spacer pairs wherein a spacer pair is taken together to form alinear moiety having from 3 through 6 contiguous atoms connecting thepoints of bonding of said spacer pair members to form a ring selectedfrom the group consisting of a cycloalkenyl ring having 5 through 8contiguous members, a partially saturated heterocyclyl ring having 5through 8 contiguous members, a heteroaryl ring having 5 through 6contiguous members, and an aryl with the provisos that no more than oneof the group consisting of spacer pairs R_(XV-4) and R_(XV-5), R_(XV-5)and R_(XV-6), R_(XV-6) and R_(XV-7), R_(XV-7) and R_(XV-8) is used atthe same time and that no more than one of the group consisting ofspacer pairs R_(XV-9) and R_(XV-10), R_(XV-10) and R_(XV-11), R_(XV-11)and R_(XV-31), R_(XV-31) and R_(XV-32), R_(XV-32) and R_(XV-12), andR_(XV-12) and R_(XV-13) are used at the same time;

[0805] R_(XV-9) and R_(XV-11), R_(XV-9) and R_(XV-12), R_(XV-9) andR_(XV-13), R_(XV-9) and R_(XV-31), R_(XV-9) and R_(XV-32), R_(XV-10) andR_(XV-12), R_(XV-10) and R_(XV-13), R_(XV-10) and R_(XV-31), R_(XV-10)and R_(XV-32), R_(XV-11) and R_(XV-12), R_(XV-11) and R_(XV-13),R_(XV-11) and R_(XV-32), R_(XV-12) and R_(XV-31), R_(XV-13) andR_(XV-31), and R_(XV-13) and R_(XV-32) are independently selected toform a spacer pair wherein said spacer pair is taken together to form alinear spacer moiety selected from the group consisting of a covalentsingle bond and a moiety having from 1 through 3 contiguous atoms toform a ring selected from the group consisting of a cycloalkyl havingfrom 3 through 8 contiguous members, a cycloalkenyl having from 5through 8 contiguous members, a saturated heterocyclyl having from 5through 8 contiguous members and a partially saturated heterocyclylhaving from 5 through 8 contiguous members with the provisos that nomore than one of said group of spacer pairs is used at the same time;

[0806] R_(XV-37) and R_(XV-38) are independently selected from the groupconsisting of hydrido, alkoxy, alkoxyalkyl, hydroxy, amino, thio, halo,haloalkyl, alkylamino, alkylthio, alkylthioalkyl, cyano, alkyl, alkenyl,haloalkoxy, and haloalkoxyalkyl.

[0807] Compounds of Formula XV are disclosed in WO 00/18723, the entiredisclosure of which is incorporated by reference.

[0808] In a preferred embodiment, the CETP inhibitor is selected fromthe following compounds of Formula XV:

[0809]3-[[3-(4-chloro-3-ethylphenoxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0810]3-[[3-(4-chloro-3-ethylphenoxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0811]3-[[3-(4-chloro-3-ethylphenoxy)phenyl](cyclopropylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0812]3-[[3-(4-chloro-3-ethylphenoxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0813]3-[[3-(4-chloro-3-ethylphenoxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0814]3-[[3-(4-chloro-3-ethylphenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0815]3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)cyclo-hexylmethyl]amino]-1,1,1-trifluoro-2-propanol;

[0816]3-[[3-(3-trifluoromethoxyphenoxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0817]3-[[3-(3-trifluoromethoxyphenoxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0818]3-[[3-(3-trifluoromethoxyphenoxy)phenyl](cyclopropylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0819]3-[[3-(3-trifluoromethoxyphenoxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0820]3-[[3-(3-trifluoromethoxyphenoxy)phenyl]](3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0821]3-[[3-(3-trifluoromethoxyphenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0822]3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0823]3-[[3-(3-isopropylphenoxy)phenyl](cyclohexylmethyl]amino]-1,1,1-trifluoro-2-propanol:

[0824]3-[[3-(3-isopropylphenoxy)phenyl](cyclopentylmethyl]amino]-1,1,1-trifluoro-2-propanol;

[0825]3-[[3-(3-isopropylphenoxy)phenyl](cyclopropylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0826] 3-[[3-(3-isopropylphenoxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0827] 3-[[3-(3-isopropylphenoxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0828] 3-[[3-(3-isopropylphenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0829]3-[[3-(3-isopropylphenoxy)phenyl][3-(1,1,2,2-tetrafluoroethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0830] 3-[[3-(2,3-dichlorophenoxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0831]3-[[3-(2,3-dichlorophenoxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0832]3-[[3-(2,3-dichlorophenoxy)phenyl](cyclopropylmethy)amino]-1,1,1-trifluoro-2-propanol;

[0833]3-[[3-(2,3-dichlorophenoxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0834] 3-[[3-(2,3-dichlorophenoxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0835] 3-[[3-(2,3-dichlorophenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0836]3-[[3-(2,3-dichlorophenoxy)phenyl][3-(1,1,2,2-tetrafluoroethoxy)cyclo-hexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0837]3-[[3-(4-fluorophenoxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0838]3-[[3-(4-fluorophenoxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0839]3-[[3-(4-fluorophenoxy)phenyl](cyclopropylmethyl)amino]-1,1,1-triflouro-2-propanol;

[0840]3-[[3-(4-fluorophenoxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0841]3-[[3-(4-fluorophenoxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0842]3-[[3-(4-fluorophenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0843]3-[[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)cyclohexylmethyl]amino]-1,1,1-trifluoro-2-propanol;

[0844]3-[[3-(3-trifluoromethoxybenzyloxy]phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0845]3-[[3-(3-trifluoromethoxybenzyloxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0846]3-[[3-(3-trifluoromethoxybenzyloxy)phenyl](cyclopropylmethyl]amino]-1,1,1-trifluoro-2-propanol;

[0847]3-[[3-(3-trifluoromethoxybenzyloxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0848]3-[[3-(3-trifluoromethoxybenzyloxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0849]3-[[3-(3-trifluoromethoxybenzyloxy]phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0850]3-[[3-(3-trifluoromethoxybenzyloxy)phenyl][3-(1,1,2,2-tetrafluoroethoxy)-cyclohexylmethyl]amino]-1,1,1-trifluoro-2-propanol;

[0851]3-[[3-(3-trifluoromethylbenzyloxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0852]3-[[3-(3-trifluoromethylbenzyloxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0853]3-[[3-(3-trifluoromethylbenzyloxy)phenyl](cyclopropylmethyl)amino]-1,1,1-trifluoro-2-propanol;

[0854]3-[[3-(3-trifluoromethylbenzyloxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0855]3-[[3-(3-trifluoromethylbenzyloxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0856]3-[[3-(3-trifluoromethylbenzyloxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0857]3-[[3-(3-trifluoromethylbenzyloxy)phenyl][3-(1,1,2,2-tetrafluoroethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0858]3-[[[(3-trifluoromethyl)phenyl]methyl](cyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0859]3-[[[(3-pentafluoroethyl)phenyl]methyl](cyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0860]3-[[[(3-trifluoromethoxy)phenyl]methyl](cyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0861]3-[[[3-(,1,2,2-tetrafluoroethoxy)phenyl]methyl](cyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0862]3-[[[(3-trifluoromethyl)phenyl]methyl](4-methylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0863]3-[[[(3-pentafluoroethyl)phenyl]methyl](4-methylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0864]3-[[[(3-trifluoromethoxy)phenyl]methyl](4-methylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0865]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](4-methylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0866]3-[[[(3-trifluoromethyl]phenyl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0867]3-[[[(3-pentafluoroethyl)phenyl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0868]3-[[[(3-trifluoromethoxy)phenyl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0869]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0870]3-[[[(3-trifluoromethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)cyclo-hexyl]amino]-1,1,1-trifluoro-2-propanol;

[0871]3-[[[(3-pentafluoroethyl)phenyl]methyl)[3-(4-chloro-3-ethylphenoxy)cyclo-hexyl]amino]-1,1,1-trifluoro-2-propanol;

[0872]3-[[[(3-trifluoromethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)cyclo-hexyl]amino]1,1,1-trifluoro-2-propanol;

[0873]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-cyclohexyl]amino]-1,1,1-trifluoro-2-propanol;

[0874]3-[[[(3-trifluoromethyl]phenyl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0875]3-[[[(3-pentafluoroethyl)phenyl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0876]3-[[[(3-trifluoromethoxy)phenyl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0877]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0878]3-[[[(3-trifloromethyl)phenyl]methyl](3-isopropoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0879]3-[[[(3-pentafluoroethyl)phenyl]methyl](3-isopropoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0880]3-[[[(3-trifluoromethoxy)phenyl]methyl](3-isopropoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0881]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3-isopropoxycyclohexyl)-amino]-1,1,1-trifluoro-2-propanol;

[0882]3-[[[(3-trifluoromethyl)phenyl]methyl](3-cyclopentyloxycyclohexyl]amino]1,1,1-trifluoro-2-propanol;

[0883]3-[[[(3-pentafluoroethyl]phenyl]methyl](3-cyclopentyloxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0884]3-[[[(3-trifluoromethoxy)phenyl]methyl](3-cyclopentyloxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0885]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3-cyclopentyloxycyclohexyl)-amino]-1,1,1-trifluoro-2-propanol;

[0886]3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-isopropoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0887]3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-cyclopentyloxycyclohexyl)-amino]-1,1,1-trifluoro-2-propanol;

[0888]3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0889]3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;

[0890]3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl][3-(4-chloro-3-ethylphenoxy)cyclo-hexyl]amino]-1,1,1-trifluoro-2-propanol;

[0891]3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl][3-(1,1,2,2-tetrafluoroethoxy)cyclo-hexyl]amino]-1,1,1-trifluoro-2-propanol;

[0892]3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-pentafluoroethylcyclohexyl)-amino]-1,1,1-trifluoro-2-propanol;

[0893]3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-trifluoromethoxycyclohexyl)-amino]-1,1,1-trifluoro-2-propanol;

[0894]3-[[[(3-trifluoromethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)propyl]-amino]-1,1,1-trifluoro-2-propanol;

[0895]3-[[[(3-pentafluoroethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)propyl]-amino]-1,1,1-trifluoro-2-propanol;

[0896]3-[[[(3-trifluoromethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)propyl]-amino]-1,1,1-trifluoro-2-propanol;

[0897]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-propyl]amino]-1,1,1-trifluoro-2-propanol;

[0898]3-[[[(3-trifluoromethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-2,2,-di-fluropropyl]amino]-1,1,1-trifluoro-2-propanol;

[0899]3-[[[(3-pentafluoroethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-2,2-di-fluropropyl]amino]-1,1,1-trifluoro-2-propanol;

[0900]3-[[[(3-trifluoromethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-2,2,-di-fluropropyl]amino]-1,1,1-trifluoro-2-propanol;

[0901]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-2,2,-difluropropyl]amino]-l1,1,1-trifluoro-2-propanol;

[0902]3-[[[(3-trifluoromethyl)phenyl]methyl][3-(isopropoxy)propyl]amino]-1,1,1-trifluoro-2-propanol;

[0903]3-[[[(3-pentafluoroethyl)phenyl]methyl][3-(isopropoxy)propyl]amino]-1,1,1-trifluoro-2-propanol;

[0904]3-[[[(3-trifluoromethoxy)phenyl]methyl][3-(isopropoxy)propyl]amino]-1,1,1-trifluoro-2-propanol;

[0905]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]]3-(isopropoxy)propyl]amino]-1,1,1-trifluoro-2-propanol;and

[0906]3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-(phenoxy)propyl]amino]-1,1,1-trifluoro-2-propanol.

[0907] Another class of CETP inhibitors that finds utility with thepresent invention consists of (R)-chiral halogenated 1-substitutedamino-(n+I)-alkanols having the Formula XVI

[0908] and pharmaceutically acceptable forms thereof, wherein:

[0909] n_(XVI) is an integer selected from 1 through 4;

[0910] X_(XVI) is oxy;

[0911] R_(XVI-1) is selected from the group consisting of haloalkyl,haloalkenyl, haloalkoxymethyl, and haloalkenyloxymethyl with the provisothat R_(XVI-1) has a higher Cahn-lngold-Prelog stereochemical systemranking than both R_(XVI-2) and (CHR_(XVI-3))_(n)-N(A_(XVI))Q_(XVI)wherein A_(XVI) is Formula XVI-(II) and Q is Formula XVI-(III);

[0912] R_(XVI-16) is selected from the group consisting of hydrido,alkyl, acyl, aroyl, heteroaroyl, trialkylsilyl, and a spacer selectedfrom the group consisting of a covalent single bond and a linear spacermoiety having a chain length of 1 to 4 atoms linked to the point ofbonding of any aromatic substituent selected from the group consistingof R_(XVI-4), R_(XVI-8), R_(XVI-9), and R_(XVI-13) to form aheterocyclyl ring having from 5 through 10 contiguous members;

[0913] D_(XVI-1), D_(XVI-2), J_(XVI-1), J_(XVI-2) and K_(XVI-1) areindependently selected from the group consisting of C, N, O, S andcovalent bond with the provisos that no more than one of D_(XVI-1),D_(XVI-2), J_(XVI-1), J_(XVI-2) and K_(XVI-1) is a covalent bond, nomore than one D_(XVI-1), D_(XVI-2), J_(XVI-1), J_(XVI-2) and K_(XVI-1)is be O, no more than one of D_(XVI-1), D_(XVI-2), J_(XVI-1), J_(XVI- 2)and K_(XVI-1) is S, one of D_(XVI-1), D_(XVI-2), J_(XVI-1), J_(XVI-2)and K_(XVI-1) must be a covalent bond when two of D_(XVI-1), D_(XVI-2),J_(XVI-1), J_(XVI-2) and K_(XVI-1) are O and S, and no more than four ofD_(XVI-1) D_(XVI-2), J_(XVI-1), J_(XVI-2) and K_(XVI-1), is N;

[0914] D_(XVI-3), D_(XVI-4), J_(XVI-3), J_(XVI-4) and K_(XVI-2) areindependently selected from the group consisting of C, N, O, S andcovalent bond with the provisos that no more than one is a covalentbond, no more than one of D_(XVI-3), D_(XVI-4), J_(XVI-3), J_(XVI-4) andK_(XVI-2) is O, no more than one of D_(XVI-3), D_(XVI-4), J_(XVI-3),J_(XVI-4) and K_(XVI-2) is S, no more than two of D_(XVI-3), D_(XVI-4),J_(XVI-3), J_(XVI-4) and K_(XVI-2) is O, and S, one of D_(XVI-3),D_(XVI-4), J_(XVI-3), J_(XVI-4) and K_(XVI-2) must be a covalent bondwhen two of D_(XVI-3), D_(XVI-4), J_(XVI-3), J_(XVI-4) and K_(XVI-2) areO and S, and no more than four of D_(XVI-3), D_(XVI-4), J_(XVI-3),J_(XVI-4) and K_(XVI-2) are N;

[0915] R_(XVI-2) is selected from the group consisting of hydrido, aryl,aralkyl, alkyl, alkenyl, alkenyloxyalkyl, haloalkyl, haloalkenyl,halocycloalkyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,halocycloalkoxy, halocycloalkoxyalkyl, perhaloaryl, perhaloaralkyl,perhaloaryloxyalkyl, heteroaryl, dicyanoalkyl, andcarboalkoxycyanoalkyl, with the proviso that R_(XVI-2) has a lowerCahn-lngold-Prelog system ranking than both R_(XVI-1) and(CHR_(XVI-3))_(n)-N(A_(XVI))Q_(XVI);

[0916] R_(XVI-3) is selected from the group consisting of hydrido,hydroxy, cyano, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl,alkoxyalkyl, heteroaryl, alkenyloxyalkyl, haloalkyl, haloalkenyl,haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl,dicyanoalkyl, carboxamide, and carboxamidoalkyl, with the provisos that(CHR_(XVI-3))_(n)-N(A_(XVI))Q_(XVI) has a lower Cahn-lngold-Prelogstereochemical system ranking than R_(XVI-1) and a higherCahn-lngold-Prelog stereochemical system ranking than R_(XVI-2);

[0917] Y_(XVI) is selected from a group consisting of a covalent singlebond, (C(R_(XVI-14))₂)_(q) wherein q is an integer selected from 1 and 2and (CH(R_(XVI-14)))_(g)-W_(XVI)-(CH(R_(XVI-14)))_(p) wherein g and pare integers independently selected from 0 and 1;

[0918] R_(XVI-14) is selected from the group consisting of hydrido,hydroxy, cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl,alkoxyalkyl, haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl,haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;

[0919] Z_(XVI) is selected from a group consisting of a covalent singlebond, (C(R_(XVI-15))₂)_(q), wherein q is an integer selected from 1 and2, and (CH(R_(XVI-15)))_(j)-W_(XVI)-(CH(R_(XVI-15)))_(k) wherein j and kare integers independently selected from 0 and 1;

[0920] W_(XVI) is selected from the group consisting of O, C(O),C(S),C(O)N(R_(XVI-14)), C(S)N(R_(XVI-14)),(R_(XVI-14))NC(O),(R_(XVI-14))NC(S), S, S(O), S(O)₂, S(O)₂N(R_(XVI-14)),(R_(XVI-14))NS(O)₂, and N(R_(XVI-14)) with the proviso that R_(XVI-14)is other than cyano;

[0921] R_(XVI-15) is selected, from the group consisting of hydrido,cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl,haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl,haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;

[0922] R_(XVI-4), R_(XVI-5), R_(XVI-6), R_(XVI-7), R_(XVI-8), R_(XVI-9),R_(XVI-10), R_(XVI-11), R_(XVI-12), and R_(XVI-13) are independentlyselected from the group consisting of hydrido, carboxy,heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl,acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl,aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl,aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl,halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl,cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl,heteroarylamino, N-heteroarylamino-N-alkylamino, heteroaralkyl,heteroarylaminoalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl,haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy,cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl,cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl,halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio,nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino,aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl,alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl,heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl,alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl,alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkylamidosulfonyl, dialkyl, amidosulfonyl, monoarylamidosulfonyl,arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl,arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl,heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl,alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl,haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky,alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl,cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo,haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl,hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl,heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturatedheterocyclyl, partially saturated heterocyclyl, heteroaryl,heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl,carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido,arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl,carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy,phosphono, phosphonoalkyl, diaralkoxyphosphono, anddiaralkoxyphosphonoalkyl with the proviso that R_(XVI-4), R_(XVI-5),R_(XVI-6), R_(XVI-7), R_(XVI-8), R_(XVI-9), R_(XVI-10), R_(XVI-11),R_(XVI-12), and R_(XVI-13) are each independently selected to maintainthe tetravalent nature of carbon, trivalent nature of nitrogen, thedivalent nature of sulfur, and the divalent nature of oxygen;

[0923] R_(XVI-4) and R_(XVI-5), R_(XVI-5) and R_(XVI-6), R_(XVI-6) andR_(XVI-7), R_(XVI-7) and R_(XVI-8), R_(XVI-9) and R_(XVI-10), R_(XVI-10)and R_(XVI-11), R_(XVI-11) and R_(XVI-12), and R_(XVI-12) and R_(XIV-13)are independently selected to form spacer pairs wherein a spacer pair istaken together to form a linear moiety having from 3 through 6contiguous atoms connecting the points of bonding of said spacer pairmembers to form a ring selected from the group consisting of acycloalkenyl ring having 5 through 8 contiguous members, a partiallysaturated heterocyclyl ring having 5 through 8 contiguous members, aheteroaryl ring having 5 through 6 contiguous members, and an aryl withthe provisos that no more than one of the group consisting of spacerpairs R_(XVI-4) and R_(XVI-5), R_(XVI-5) and R_(XVI-6), R_(XVI-6) andR_(XVI-7), and R_(XVI-7) and R_(XVI-8) is used at the same time and thatno more than one of the group consisting of spacer pairs R_(XVI-9) andR_(XVI-10), R_(XVI-10) and R_(XVI-11), R_(XVI-11) and R_(XVI-12), andR_(XVI-12) and R_(XVI-13) can be used at the same time;

[0924] R_(XVI-4) and R_(XVI-9), R_(XVI-4) and R_(XVI-13), R_(XVI-8) andR_(XVI-9), and R_(XVI-8) and R_(XVI-13) is independently selected toform a spacer pair wherein said spacer pair is taken together to form alinear moiety wherein said linear moiety forms a ring selected from thegroup consisting of a partially saturated heterocyclyl ring having from5 through 8 contiguous members and a heteroaryl ring having from 5through 6 contiguous members with the proviso that no more than one ofthe group consisting of spacer pairs R_(XVI-4) and R_(XVI-9), R_(XVI-4)and R_(XVI-13), R_(XVI-8) and R_(XVI-9), and R_(XVI-8) and R_(XVI-13) isused at the same time.

[0925] Compounds of Formula XVI are disclosed in WO 00/18724, the entiredisclosure of which is incorporated by reference.

[0926] In a preferred embodiment, the CETP inhibitor is selected fromthe following compounds of Formula XVI:

[0927](2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0928](2R)-3-[[3-(3-isopropylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0929](2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0930](2R)-3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0931](2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0932](2R)-3-[[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0933](2R)-3-[[3-(4-methylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0934](2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0935](2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-etrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0936](2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0937](2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0938](2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0939](2R)-3-[[3-(3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0940](2R)-3-[[3-(3-t-butylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol:

[0941](2R)-3-[[3-(3-methylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0942](2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0943](2R)-3-[[3-(phenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0944](2R)-3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0945](2R)-3-[[[3-(1,1,2,2,-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethoxy)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0946](2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoro-methyl)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0947](2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0948](2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethylthio)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0949](2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0950](2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0951](2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0952](2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0953](2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0954](2R)-3-[[[3-(3-trifuoromethylthio)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0955](2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0956](2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0957](2R)-3-[[3-(3-isopropylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0958](2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0959](2R)-3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0960](2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0961](2R)-3-[[3-(4-fluorophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0962](2R)-3-[[3-(4-methylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0963](2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0964](2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0965] (2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(pentafluoroethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0966](2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0967] (2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0968] (2R)-3-[[3-(3-ethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0969] (2R)-3-[[3-(3-t-butylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0970] (2R)-3-[[3-(3-methylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0971](2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0972](2R)-3-[[3-(phenoxy)phenyl][[3(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0973](2R)-3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0974](2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0975](2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethyl)-phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0976](2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0977](2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0978](2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3,5-difiuorophenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[0979](2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[cyclohexylmethoxy]phenyl]-amino]-1,1,1-trifluoro-2-propanol;

[0980](2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0981](2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0982](2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0983](2R)-3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0984](2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(pentafluoroethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0985](2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0986](2R)-3-[[3-(3-isopropylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0987](2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0988] (2R)-3-[[3-(3-(²7furyl)phenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0989] (2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0990] (2R)-3-[[3-(4-fluorophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0991] (2R)-3-[[3-(4-methylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1,-trifluoro-2-propanol;

[0992](2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0993](2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0994] (2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(heptafluoropropyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0995](2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[0996] (2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[0997] (2R)-3-[[3-(3-ethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0998] (2R)-3-[[3-(3-t-butylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[0999] (2R)-3-[[3-(3-methylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1000](2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1001] (2R)-3-[[3-(phenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1002](2R)-3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1003](2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1004](2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethyl)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1005](2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3,5-dimethylphenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1006](2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethylthio)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1007](2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3,5-difluorophenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1008](2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[cyclohexylmethoxy]phenyl]-amino]-1,1,1-trifluoro-2-propanol;

[1009](2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1010](2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1011](2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1012](2R)-3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1013](2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(heptafluoropropyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1014]5(2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1015](2R)-3-[[3-(3-isopropylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1016](2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1017](2R)-3-[[3-(3-(2-furyl)phenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1018](2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1019](2R)-3-[[3-(4-fluorophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-3-propanol;

[1020](2R)-3-[[3-(4-methylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1021](2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1022](2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1023](2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[2-fluoro-5-(trifluoro-methyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1024](2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1025](2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1026](2R)-3-[[3-(3-ethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[1027](2R)-3-[[3-(3-t-butylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[1028](2R)-3-[[3-(3-methylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[1029]

[1030](2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1031] (2R)-3-[[3-(phenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1032] (2R)-3-[[3-[3-(N,N-dimethylamino,phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1033](2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-3-propanol;

[1034](2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethyl)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1035](2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1036](2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1037](2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1038](2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[cyclohexylmethoxyl-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1039](2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1040](2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1041](2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1042](2R)-3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1043](2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[2-fluoro-5-(trifluoro-methyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1044](2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1045](2R)-3-[[3-(3-isopropylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]l-1,1,1-trifluoro-2-propanol;

[1046](2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[2-flouro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1047](2R)-3-[[3-(3-(2-furyl)phenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1048](2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1049](2R)-3-[[3-(4-fluorophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1050](2R)-3-[[3-(4-methylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1051](2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1052](2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1053] (2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1054](2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1055](2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;

[1056](2R)-3-[[3-(3-ethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[1057](2R)-3-[[3-(3-t-butylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[1058](2R)-3-[[3-(3-methylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;

[1059](2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1060] (2R)-3-[[3-(phenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1061](2R)-3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1062](2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1063](3R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethyl)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1064](2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1065](2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)-phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1066](2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1067](2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;

[1068](2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[2-fluoro-4-(trifluoromethyl)-10phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1069](2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1070](2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

[1071](2R)-3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;and

[1072](2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol.

[1073] Another class of CETP inhibitors that finds utility with thepresent invention consists of quinolines of Formula XVII

[1074] and pharmaceutically acceptable forms thereof, wherein:

[1075] A_(XVII) denotes an aryl containing 6 to 10 carbon atoms, whichis optionally substituted with up to five identical or differentsubstituents in the form of a halogen, nitro, hydroxyl, trifluoromethyl,trifluoromethoxy or a straight-chain or branched alkyl, acyl,hydroxyalkyl or alkoxy containing up to 7 carbon atoms each, or in theform of a group according to the formula —NR_(XVII-4)R_(XVII-5), whereinR_(XVII-4) and R_(XVII-5) are identical or different and denote ahydrogen, phenyl or a straight-chain or branched alkyl containing up to6 carbon atoms,

[1076] D_(XVII) denotes an aryl containing 6 to 10 carbon atoms, whichis optionally substituted with a phenyl, nitro, halogen, trifluoromethylor trifluoromethoxy, or a radical according to the formula

[1077] wherein

[1078] R_(XVII-6), R_(XVII-7), R_(XVII-10) denote, independently fromone another, a cycloalkyl containing 3 to 6 carbon atoms, or an arylcontaining 6 to 10 carbon atom or a 5- to 7-membered, optionallybenzo-condensed, saturated or unsaturated, mono-, bi- or tricyclicheterocycle containing up to 4 heteroatoms from the series of S, Nand/or O, wherein the rings are optionally substituted, in the case ofthe nitrogen-containing rings also via the N function, with up to fiveidentical or different substituents in the form of a halogen,trifluoromethyl, nitro, hydroxyl, cyano, carboxyl, trifluoromethoxy, astraight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxyor alkoxycarbonyl containing up to 6 carbon atoms each, an aryl ortrifluoromethyl-substituted aryl containing 6 to 10 carbon atoms each,or an optionally benzo-condensed, aromatic 5- to 7-membered heterocyclecontaining up to 3 heteoatoms from the series of S, N and/or O, and/orin the form of a group according to the formula —OR_(XVII-11),—SR_(XVII-12), —SO₂R_(XVII-13), or —NR_(XVII-14), R_(XVII-15);

[1079] R_(XVII-11), R_(XVII-12), and R_(XVII-13) denote, independentlyfrom one another, an aryl containing 6 to 10 carbon atoms, which is inturn substituted with up to two identical or different substituents inthe form of a phenyl, halogen or a straight-chain or branched alkylcontaining up to 6 carbon atoms,

[1080] R_(XVII-14) and R_(XVII-15) are identical or different and havethe meaning of R_(XVII-4) and R_(XVII-5) given above, or

[1081] R_(XVII-6) and/or R_(XVII-7) denote a radical according to theformula

[1082] R_(XVII-8) denotes a hydrogen or halogen, and

[1083] R_(XVII-9) denotes a hydrogen, halogen, azido, trifluoromethyl,hydroxyl, trifluoromethoxy, a straight-chain or branched alkoxy or alkylcontaining up to 6 carbon atoms each, or a radical according to theformula NR_(XVII-16)R_(XVII-17);

[1084] R_(XVII-16) and R_(XVII-17) are identical or different and havethe meaning of R_(XVII-4) and R_(XVII-5) above; or

[1085] R_(XVII-8) and R_(XVII-9) together form a radical according tothe formula ═O or ═NR_(XVII-18);

[1086] R_(XVII-18) denotes a hydrogen or a straight-chain or branchedalkyl, alkoxy or acyl containing up to 6 carbon atoms each;

[1087] L_(XVII) denotes a straight-chain or branched alkylene oralkenylene chain containing up to 8 carbon atoms each, which areoptionally substituted with up to two hydroxyl groups;

[1088] T_(XVII) and X_(XVII) are identical-or different and denote astraight-chain or branched alkylene chain containing up to 8 carbonatoms; or

[1089] T_(XVII) and X_(XVII) denotes a bond;

[1090] V_(XVII) denotes an oxygen or sulfur atom or —NR_(XVII-19);

[1091] R_(XVII-19) denotes a hydrogen or a straight-chain or branchedalkyl containing up to 6 carbon atoms or a phenyl;

[1092] E_(XVII) denotes a cycloalkyl containing 3 to 8 carbon atoms, ora straight-chain or branched alkyl containing up to 8 carbon atoms,which is optionally substituted with a cycloalkyl containing 3 to 8carbon atoms or a hydroxyl, or a phenyl, which is optionally substitutedwith a halogen or trifluoromethyl;

[1093] R_(XVII-1) and R_(XVII-2) are identical or different and denote acycloalkyl containing 3 to 8 carbon atoms, hydrogen, nitro, halogen,trifluoromethyl, trifluoromethoxy, carboxy, hydroxy, cyano, astraight-chain or branched acyl, alkoxycarbonyl or alkoxy with up to 6carbon atoms, or NR_(XVII-20)R_(XVII-21);

[1094] R_(XVII-20) and R_(XVII-21) are identical or different and denotehydrogen, phenyl, or a straight-chain or branched alkyl with up to 6carbon atoms; and or

[1095] R_(XVII-1) and/or R_(XVII-2) are straight-chain or branched alkylwith up to 6 carbon atoms, optionally substituted with halogen,trifluoromethoxy, hydroxy, or a straight-chain or branched alkoxy withup to 4 carbon atoms, aryl containing 6-10 carbon atoms optionallysubstituted with up to five of the same or different substituentsselected from halogen, cyano, hydroxy, trifluoromethyl,trifluoromethoxy, nitro, straight-chain or branched alkyl, acyl,hydroxyalkyl, alkoxy with up to 7 carbon atoms andNR_(XVII-22)R_(XVII-23);

[1096] R_(XVII-22) and R_(XVII-23) are identical or different and denotehydrogen, phenyl or a straight-chain or branched akyl up to 6 carbonatoms; and/or

[1097] R_(XVII-1) and R_(XVII-2) taken together form a straight-chain orbranched alkene or alkane with up to 6 carbon atoms optionallysubstituted with halogen, trifluoromethyl, hydroxy or straight-chain orbranched alkoxy with up to 5 carbon atoms;

[1098] R_(XVII-3) denotes hydrogen, a straight-chain or branched acylwith up to 20 carbon atoms, a benzoyl optionally substituted withhalogen, trifluoromethyl, nitro or trifluoromethoxy, a straight-chainedor branched fluoroacyl with up to 8 carbon atoms and 7 fluoro atoms, acycloalkyl with 3 to 7 carbon atoms, a straight chained or branchedalkyl with up to 8 carbon atoms optionally substituted with hydroxyl, astraight-chained or branched alkoxy with up to 6 carbon atoms optionallysubstituted with phenyl which may in turn be substituted with halogen,nitro, trifluoromethyl, trifluoromethoxy, or phenyl or a tetrazolsubstitued phenyl, and/or an alkyl that is optionally substituted with agroup according to the formula —OR_(XVII-24);

[1099] R_(XVII-24) is a straight-chained or branched acyl with up to 4carbon atoms or benzyl.

[1100] Compounds of Formula XVII are disclosed in WO 98/39299, theentire disclosure is incorporated by reference.

[1101] Another class of CETP inhibitors that finds utility with thepresent invention consists of 4-Phenyltetrahydroquinolines of FormulaXVIII

[1102] N oxides thereof, and pharmaceutically acceptable forms thereof,wherein:

[1103] A_(XVIII) denotes a phenyl optionally substituted with up to twoidentical or different substituents in the form of halogen,trifluoromethyl or a straight-chain or branched alkyl or alkoxycontaining up to three carbon atoms;

[1104] D_(XVIII) denotes the formula

[1105] R_(XVIII-5) and R_(XVIII-6) are taken together to form ═O; or

[1106] R_(XVIII-5) denotes hydrogen and R_(XVIII-6)denotes halogen orhydrogen; or

[1107] R_(XVIII-5) and R_(XVIII-6) denote hydrogen;

[1108] R_(XVIII-7) and R_(XVIII-8) are identical or different and denotephenyl, naphthyl, benzothiazolyl, quinolinyl, pyrimidyl or pyridyl withup to four identical or different substituents in the form of halogen,trifluoromethyl, nitro, cyano, trifluoromethoxy, —SO₂—CH₃ orNR_(XVIII-9)R_(XVIII-10);

[1109] R_(XVIII-9) and R_(XVIII-10) are identical or different anddenote hydrogen or a straight-chained or branched alkyl of up to threecarbon atoms;

[1110] E_(XVIII) denotes a cycloalkyl of from three to six carbon atomsor a straight-chained or branched alkyl of up to eight carbon atoms;

[1111] R_(XVIII-1) denotes hydroxy;

[1112] R_(XVIII-2) denotes hydrogen or methyl;

[1113] R_(XVIII-3) and R_(XVIII-4) are identical or different and denotestraight-chained or branched alkyl of up to three carbon atoms; or

[1114] R_(XVIII-3) and R_(XVIII-4) taken together form an alkenylenemade up of between two and four carbon atoms.

[1115] Compounds of Formula XVIII are disclosed in WO 99/15504, theentire disclosure of which is incorporated by reference.

[1116] Another class of CETP inhibitors that finds utility with thepresent invention consists of aminoethanol derivatives of Formula XIX

[1117] and pharmaceutically acceptable forms thereof, wherein:Ar_(XIX-1) denotes an aromatic ring group that may contain asubstituting group; Ar_(XIX-2) denotes an aromatic ring group that maycontain a substituting group; R_(XIX) denotes an acyl group; R′_(XIX)denotes a hydrogen atom or hydrocarbon group that may contain asubstituting group; and OR″_(XIX) denotes a hydroxyl group that may beprotected.

[1118] Compounds of Formula XIX are disclosed in WO 2002/059077, theentire disclosure of which is incorporated by reference.

[1119] In a preferred embodiment, the CETP inhibitor is selected fromthe following compounds of Formula XIX or their salts:

[1120] N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[4-(trifluoromethyl)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cyclopentene-1-carboxamide,

[1121]4-fluoro-N-((1R,2S)-2-(4-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-1-naphthalenecarboxamide;

[1122]N-[(1R,2S)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7-dihydro-5H-benzo[a]cyclopentene-1-carboxamide;

[1123] N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-5,6-dihydronaphthalene-1-carboxamide;

[1124]N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-1-carboxamide;

[1125]4-fluoro-N-[(1R,2S)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]naphthalene-1-carboxamide;

[1126]N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl]-5,6,7,8-tetrahydrobenzo[a]cyclooctene-1-carboxamide;

[1127] N-[(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-(4-isopropylbenzyl)ethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide;

[1128]N-((1RS,2SR)-2-(3-fluorophenyl)-2-hydroxy-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide;

[1129]N-((1RS,2SR)-2-hydroxy-2-(4-phenoxyphenyl)-1-((4-(trifluoromethyl)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide;

[1130]N-[(1RS,2SR)-2-(4-chlorophenyl)-2-hydroxy-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide;

[1131]N-((1RS,2SR)-2-hydroxy-2-(4-phenyloxy)phenyl)-1-((3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide;

[1132]N-((1RS,2SR)-2-(4-((4-chloro-3-ethylphenyl)oxy)phenyl)-2-hydroxy-1-((3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide;

[1133]N-((1RS,2SR)-2-(2-fluoropyridine-4-yl)-2-hydroxy-1-((3-((1,1,2,2-tetrafluoroethoxy)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide;

[1134]N-((1RS,2RS)-2-(6-fluoropyridine-2-yl)-2-hydroxy-1-((3-((1,1,2,2-tetrafluoroethoxy)phenyl)methyl)ethyl)-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide;

[1135]N-[(1RS,2SR)-1-(4-tert-butylbenzyl)-2-(3-chlorophenyl)-2-hydroxyethyl]-5-chloro-1-napthoamide;

[1136]4-fluoro-N-{(1RS,2SR)-2-(4-fluorophenyl)-2-hydroxy-1-[(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)methyl]ethyl}-1-naphthoamide.

[1137] In a preferred embodiment, the CETP inhibitor is[2R,4S]-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester, also known as torcetrapib. Torcetrapib is shown by thefollowing Formula

[1138] CETP inhibitors, in particular torcetrapib, and methods forpreparing such compounds are disclosed in detail in U.S. Pat. Nos.6,197,786 and 6,313,142, in PCT Application Nos. WO 01/40190A1, WO02/088085A2, and WO 02/088069A2, the disclosures of which are hereinincorporated by reference. Torcetrapib has an unusually low solubilityin aqueous environments such as the lumenal fluid of the human GI tract.The aqueous solubility of torceptrapib is less than about 0.04 μg/ml.Torcetrapib must be presented to the GI tract in a solubility-enhancedform in order to achieve a sufficient drug concentration in the GI tractin order to achieve sufficient absorption into the blood to elicit thedesired therapeutic effect.

CONCENTRATION ENHANCEMENT

[1139] The polymer used in the solid amorphous dispersion is a“concentration-enhancing polymer,” meaning that it meets at least one,and preferably both, of the following conditions. The first condition isthat the concentration-enhancing polymer increases the maximum drugconcentration (MDC) of the CETP inhibitor provided by either the solidamorphous dispersion alone, or the dosage form, in the environment ofuse relative to a control composition. That is, once the solid amorphousdispersion or dosage form is introduced into an environment of use, thepolymer increases the aqueous concentration in the use environment ofCETP inhibitor relative to the control composition. It is to beunderstood that the control composition is free from solubilizers orother components that would materially affect the solubility of the CETPinhibitor, and that the CETP inhibitor is in solid form in the controlcomposition. The control composition is conventionally the undispersed,or crystalline form, of the CETP inhibitor alone. In the case of adosage form, the control composition is the same as the dosage form,except that the solid amorphous dispersion is replaced by undispersedCETP inhibitor and no polymer, the amount of CETP inhibitor beingequivalent to the amount in the solid amorphous dispersion. Preferably,the polymer increases the MDC of the CETP inhibitor in the aqueous useenvironment by at least 1.25-fold relative to a control composition,more preferably by at least 2-fold, and most preferably by at least3-fold. Surprisingly, the polymer may achieve extremely largeenhancements in aqueous concentration. In some cases, the MDC of CETPinhibitor provided by the test composition is at least 10-fold, at least50-fold, at least 200-fold, at least 500-fold, to more than 1000-foldthe equilibrium concentration provided by the control composition, wherethe test composition is either the solid amorphous dispersion or thedosage form.

[1140] The second condition is that the concentration-enhancing polymerincreases the area under the concentration versus time curve (AUC) ofthe CETP inhibitor in the environment of use relative to a controlcomposition consisting of the undispersed CETP inhibitor but no polymer.(The calculation of an AUC is a well-known procedure in thepharmaceutical arts and is described, for example, in Welling,“Pharmacokinetics Processes and Mathematics,” ACS Monograph 185 (1986).)More specifically, in the environment of use, the solid amorphousdispersion comprising the CETP inhibitor and the concentration-enhancingpolymer provides an AUC for any 90-minute period of from about 0 toabout 270 minutes following introduction to the use environment that isat least 1.25-fold that of the control composition described above.Preferably, the AUC provided by the solid amorphous dispersion is atleast 2-fold, more preferably at least 3-fold that of the controlcomposition. For some CETP inhibitors, the compositions of the presentinvention may provide an AUC value that is at least 5-fold, at least25-fold, at least 100-fold, and even more than 250-fold that of acontrol composition as described above.

[1141] As previously mentioned, a “use environment” can be either the invivo environment such as the GI tract of an animal, particularly ahuman, or the in vitro environment of a test solution, such as phosphatebuffered saline (PBS) solution or Model Fasted Duodenal (MFD) solution.

[1142] Concentration enhancement may be determined through either invivo tests or through in vitro dissolution tests. A composition of thepresent invention meets the concentration enhancement criteria in atleast one of the above test environments.

[1143] Where the use environment is the GI tract of an animal, dissolveddrug concentration may be determined by a conventional method known inthe art. One method is a deconvolution method. In this method, the serumor plasma drug concentration is plotted along the ordinate (y-axis)against the blood sample time along the abscissa (x-axis). The data maythen be analyzed to determine drug release rates in the GI tract usingany conventional analysis, such as the Wagner-Nelson or Loo-Riegelmananalysis. See also Welling, “Pharmacokinetics: Processes andMathematics” (ACS Monograph 185, Amer. Chem. Soc., Washington, D.C.,1986). Treatment of the data in this manner yields an apparent in vivodrug release profile. Another method is to intubate the patient andperiodically sample the GI tract directly.

[1144] The solid amorphous dispersions of CETP inhibitor andconcentration-enhancing polymer used in the inventive dosage formsprovide enhanced concentration of the dissolved CETP inhibitor in invitro dissolution tests. It has been determined that enhanced drugconcentration in in vitro dissolution tests in MFD solution or in PBSsolution is a good indicator of in vivo performance and bioavailability.An appropriate PBS solution is an aqueous solution comprising 20 mMNa₂HPO₄, 47 mM KH₂PO₄, 87 mM NaCl, and 0.2 mM KCl, adjusted to pH 6.5with NaOH. An appropriate MFD solution is the same PBS solution whereinthere is also present 7.3 mM sodium taurocholic acid and 1.4 mM of1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine. In particular, acomposition formed by the inventive method can be dissolution-tested byadding it to MFD or PBS solution and agitating to promote dissolution.

[1145] An in vitro test to evaluate enhanced CETP inhibitorconcentration in aqueous solution can be conducted by (1) adding withagitation a sufficient quantity of control composition, typically theundispersed CETP inhibitor alone, to the in vitro test medium, such asan MFD or a PBS solution, to achieve equilibrium concentration of theCETP inhibitor; (2) in a separate test, adding with agitation asufficient quantity of test composition (e.g., the solid amorphousdispersion of CETP inhibitor and polymer or dosage form) in the sametest medium, such that if all the CETP inhibitor dissolved, thetheoretical concentration of CETP inhibitor would exceed the equilibriumconcentration of the CETP inhibitor by a factor of at least 2, andpreferably by a factor of at least 10; and (3) comparing the measuredMDC and/or aqueous AUC of the test composition in the test medium withthe equilibrium concentration, and/or with the aqueous AUC of thecontrol composition. In conducting such a dissolution test, the amountof test composition or control composition used is an amount such thatif all of the CETP inhibitor dissolved the CETP inhibitor concentrationwould be at least 2-fold, preferably at least 10-fold, and mostpreferably at least 100-fold that of the equilibrium concentration.Indeed, for some extremely insoluble CETP inhibitors, in order toidentify the MDC achieved it may be necessary to use an amount of testcomposition such that if all of the CETP inhibitor dissolved, the CETPinhibitor concentration would be 1000-fold or even more, that of theequilibrium concentration of the CETP inhibitor.

[1146] The concentration of dissolved CETP inhibitor is typicallymeasured as a function of time by sampling the test medium and plottingCETP inhibitor concentration in the test medium vs. time so that the MDCcan be ascertained. The MDC is taken to be the maximum value ofdissolved CETP inhibitor measured over the duration of the test. Theaqueous AUC is calculated by integrating the concentration versus timecurve over any 90-minute time period between the time of introduction ofthe composition into the aqueous use environment (when time equals zero)and 270 minutes following introduction to the use environment (when timeequals 270 minutes). Typically, when the composition reaches its MDCrapidly, in say less than about 30 minutes, the time interval used tocalculate AUC is from time equals zero to time equals 90 minutes.However, if the AUC of a composition over any 90-minute time perioddescribed above meets the criterion of this invention, then thecomposition formed is considered to be within the scope of thisinvention.

[1147] To avoid large drug particulates that would give an erroneousdetermination, the test solution is either filtered or centrifuged.“Dissolved drug” is typically taken as that material that either passesa 0.45 μm syringe filter or, alternatively, the material that remains inthe supernatant following centrifugation. Filtration can be conductedusing a 13 mm, 0.45 μm polyvinylidine difluoride syringe filter sold byScientific Resources under the trademark TITAN®. Centrifugation istypically carried out in a polypropylene microcentrifuge tube bycentrifuging at 13,000 G for 60 seconds. Other similar filtration orcentrifugation methods can be employed and useful results obtained. Forexample, using other types of microfilters may yield values somewhathigher or lower (±10-40%) than that obtained with the filter specifiedabove but will still allow identification of preferred dispersions. Itshould be recognized that this definition of “dissolved drug”encompasses not only monomeric solvated drug molecules but also a widerange of species such as polymer/drug assemblies that have submicrondimensions such as drug aggregates, aggregates of mixtures of polymerand drug, micelles, polymeric micelles, colloidal particles ornanocrystals, polymer/drug complexes, and other such drug-containingspecies that are present in the filtrate or supernatant in the specifieddissolution test.

[1148] In another separate aspect, the solid amorphous dispersions, whendosed orally to a human or other animal in a fasted state, providesimproved concentration of dissolved CETP inhibitor in the blood relativeto the control composition. The solid amorphous dispersion achieves ahigher maximum drug concentration (C_(max)) of the CETP inhibitor in theblood (serum or plasma) relative to a control composition consisting ofan equivalent amount of crystalline drug in its lowest energy form, oramorphous form if the crystalline form is unknown. It is to beunderstood that the control composition is free from solubilizers orother components that would materially affect the solubility of the CETPinhibitor. Preferably, the solid amorphous dispersion provides a C_(max)of CETP inhibitor in the blood that is at least 1.25-fold that providedby the control composition, more preferably by at least 2-fold, and mostpreferably by at least 3-fold.

[1149] Alternatively, the solid amorphous dispersions, when dosed orallyto a human or other animal, provide an AUC in CETP inhibitorconcentration in the blood that is at least about 1.25-fold, preferablyat least about 2-fold, preferably at least about 3-fold, preferably atleast about 4-fold, preferably at least about 6-fold, preferably atleast 10-fold, and even more preferably at least about 20-fold thatobserved when a control composition consisting of an equivalent quantityof undispersed CETP inhibitor is dosed. It is noted that suchcompositions can also be said to have a relative bioavailability of fromabout 1.25-fold to about 20-fold that of the control composition.

[1150] Relative bioavailability of CETP inhibitors in the solidamorphous dispersions or dosage forms can be tested in vivo in animalsor humans using conventional methods for making such a determination. Anin vivo test, such as a crossover study, may be used to determinewhether a composition of CETP inhibitor and concentration-enhancingpolymer provides an enhanced relative bioavailability compared with acontrol composition as described above. In an in vivo crossover study atest composition of a solid amorphous dispersion of a CETP inhibitor andpolymer, or dosage form, is dosed to half a group of test subjects and,after an appropriate washout period (e.g., one week) the same subjectsare dosed with a control composition. The other half of the group isdosed with the control composition first, followed by the testcomposition. The relative bioavailability is measured as theconcentration in the blood (serum or plasma) versus time area under thecurve (AUC) determined for the test group divided by the AUC in theblood provided by the control composition. Preferably, this test/controlratio is determined for each subject, and then the ratios are averagedover all subjects in the study. In vivo determinations of AUC can bemade by plotting the serum or plasma concentration of drug along theordinate (y-axis) against time along the abscissa (x-axis). Tofacilitate dosing, a dosing vehicle may be used to administer the dose.The dosing vehicle is preferably water, but may also contain materialsfor suspending the test or control composition, provided these materialsdo not dissolve the composition or change the drug solubility in vivo.

PREPARATION OF DISPERSIONS

[1151] The solid amorphous dispersions of CETP inhibitor and neutral orneutralized acidic polymer may be made according to any conventionalprocess for forming solid amorphous dispersions that results in at leasta major portion (at least 60%) of the CETP inhibitor being in theamorphous state. Such processes include mechanical, thermal and solventprocesses. Exemplary mechanical processes include milling and extrusion;melt processes include high temperature fusion, solvent-modified fusionand melt-congeal processes; and solvent processes include non-solventprecipitation, spray-coating and spray-drying. See, for example, thefollowing U.S. Patents, the pertinent disclosures of which areincorporated herein by reference: U.S. Pat. Nos. 5,456,923 and5,939,099, which describe forming dispersions by extrusion processes;U.S. Pat. Nos. 5,340,591 and 4,673,564, which describe formingdispersions by milling processes; and U.S. Pat. Nos. 5,707,646 and4,894,235, which describe forming dispersions by melt congeal processes.

[1152] When the CETP inhibitor has a relatively low melting point,typically less than about 200° C. and preferably less than about 150°C., the use of a melt-congeal or melt-extrusion process is advantageous.In such processes, a molten mixture comprising the CETP inhibitor andconcentration-enhancing polymer is rapidly cooled to solidify the moltenmixture to form a solid amorphous dispersion. By “molten mixture” ismeant that the mixture comprising the CETP inhibitor andconcentration-enhancing polymer is heated sufficiently that it becomessufficiently fluid that the CETP inhibitor substantially disperses inone or more of the concentration-enhancing polymers and otherexcipients. Generally, this requires that the mixture be heated to about10° C. or more above the melting point of the lowest melting excipientor CETP inhibitor in the composition. The CETP inhibitor may exist inthe molten mixture as a pure phase, as a solution of CETP inhibitorhomogeneously distributed throughout the molten mixture, or anycombination of these states or those states that lie intermediatebetween them. The molten mixture is preferably substantially homogeneousso that the CETP inhibitor is dispersed as homogeneously as possiblethroughout the molten mixture. When the temperature of the moltenmixture is below the melting point of both the CETP inhibitor and theconcentration-enhancing polymer, the molten excipients,concentration-enhancing polymer, and CETP inhibitor are preferablysufficiently soluble in each other that a substantial portion of theCETP inhibitor disperses in the concentration-enhancing polymer orexcipients. It is often preferred that the mixture be heated above thelower of the melting points of the concentration-enhancing polymer andthe CETP inhibitor. It should be noted that many concentration-enhancingpolymers are amorphous. In such cases, melting point refers to thesoftening point of the polymer. Thus, although the term “melting point”generally refers specifically to the temperature at which a crystallinematerial transitions from its crystalline to its liquid state, as usedherein, the term is used more broadly, referring to the heating of anymaterial or mixture of materials sufficiently that it becomes fluid in amanner similar to a crystalline material in the fluid state.

[1153] Generally, the processing temperature may vary from 50° C. up toabout 200° C. or higher, depending on the melting point of the CETPinhibitor and polymer, the latter being a function of the polymer gradeselected. However, the processing temperature should not be so high thatan unacceptable level of degradation of the CETP inhibitor or polymeroccurs. In some cases, the molten mixture should be formed under aninert atmosphere to prevent degradation of the CETP inhibitor and/orpolymer at the processing temperature. When relatively high temperaturesare used, it is often preferable to minimize the time that the mixtureis at the elevated temperature to minimize degradation.

[1154] The molten mixture may also include an excipient that will reducethe melting temperature of the molten mixture, thereby allowingprocessing at a lower temperature. When such excipients have lowvolatility and substantially remain in the mixture upon solidification,they generally can comprise up to 30 wt % of the molten mixture. Forexample, a plasticizer may be added to the mixture to reduce the meltingtemperature of the polymer. Examples of plasticizers include water,triethylcitrate, triacetin, and dibutyl sebacate. Volatile agents thatdissolve or swell the polymer, such as acetone, water, methanol andethyl acetate, may also be added to reduce the melting point of themolten mixture. When such volatile excipients are added, at least aportion, up to essentially all of such excipients may evaporate in theprocess of or following conversion of the molten mixture to a solidmixture. In such cases, the processing may be considered to be acombination of solvent processing and melt-congealing or melt-extrusion.Removal of such volatile excipients from the molten mixture can beaccomplished by breaking up or atomizing the molten mixture into smalldroplets and contacting the droplets with a fluid so that the dropletsboth cool and lose all or part of the volatile excipient. Examples ofother excipients that can be added to the mixture to reduce theprocessing temperature include low molecular weight polymers oroligomers, such as polyethylene glycol, polyvinylpyrrolidone, andpoloxamers; fats and oils, including mono-, di-, and triglycerides;natural and synthetic waxes, such as Carnauba wax, beeswax,microcrystalline wax, castor wax, and paraffin wax; long chain alcohols,such as cetyl alcohol and stearyl alcohol; and long chain fatty acids,such as stearic acid. As mentioned above, when the excipient added isvolatile, it may be removed from the mixture while still molten orfollowing solidification to form the solid amorphous dispersion.

[1155] Virtually any process may be used to form the molten mixture. Onemethod involves melting the concentration-enhancing polymer in a vesseland then adding the CETP inhibitor to the molten polymer. Another methodinvolves melting the CETP inhibitor in a vessel and then adding theconcentration-enhancing polymer. In yet another method, a solid blend ofthe CETP inhibitor and concentration-enhancing polymer may be added to avessel and the blend heated to form the molten mixture.

[1156] Once the molten mixture is formed, it may be mixed to ensure theCETP inhibitor is homogeneously distributed throughout the moltenmixture. Such mixing may be done using mechanical means, such asoverhead mixers, magnetically driven mixers and stir bars, planetarymixers, and homogenizers. Optionally, when the molten mixture is formedin a vessel, the contents of the vessel can be pumped out of the vesseland through an in-line or static mixer and then returned to the vessel.The amount of shear used to mix the molten mixture should besufficiently high to ensure uniform distribution of the CETP inhibitorin the-molten mixture. The molten mixture can be mixed from a fewminutes to several hours, the mixing time depending on the viscosity ofthe mixture and the solubility of the CETP inhibitor and the presence ofoptional excipients in the concentration-enhancing polymer.

[1157] Yet another method of preparing the molten mixture is to use twovessels, melting the CETP inhibitor in the first vessel and theconcentration-enhancing polymer in a second vessel. The two melts arethen pumped through an in-line static mixer or extruder to produce themolten mixture that is then rapidly solidified.

[1158] Still another method of preparing the molten mixture is by theuse of an extruder, such as a single-screw or twin-screw extruder, bothwell known in the art. In such devices, a solid feed of the compositionis fed to the extruder, whereby the combination of heat and shear forcesproduce a uniformly mixed molten mixture, which can then be rapidlysolidified to form the solid amorphous dispersion. The solid feed can beprepared using methods well known in the art for obtaining solidmixtures with high content uniformity. Alternatively, the extruder maybe equipped with two feeders, allowing the CETP inhibitor to be fed tothe extruder through one feeder and the polymer through the other. Otherexcipients to reduce the processing temperature as described above maybe included in the solid feed, or in the case of liquid excipients, suchas water, may be injected into the extruder using methods well known inthe art.

[1159] The extruder should be designed so that it produces a moltenmixture with the CETP inhibitor uniformly distributed throughout thecomposition. Various zones in the extruder should be heated toappropriate temperatures to obtain the desired extrudate temperature aswell as the desired degree of mixing or shear, using procedures wellknown in the art.

[1160] When the CETP inhibitor has a high solubility in theconcentration-enhancing polymer, a lower amount of mechanical energywill be required to form the solid amorphous dispersion. In the casewhere the melting point of the undispersed CETP inhibitor is greaterthan the melting point of the undispersed concentration-enhancingpolymer, the processing temperature may be below the melting temperatureof the undispersed CETP inhibitor but greater than the melting point ofthe polymer, since the CETP inhibitor will dissolve into the moltenpolymer. When the melting point of the undispersed CETP inhibitor isless than the melting point of the undispersed concentration-enhancingpolymer, the processing temperature may be above the melting point ofthe undispersed CETP inhibitor but below the melting point of theundispersed concentration-enhancing polymer since the molten CETPinhibitor will dissolve in or be absorbed into the polymer.

[1161] When the CETP inhibitor has a low solubility in the polymer, ahigher amount of mechanical energy may be required to form the solidamorphous dispersion. Here, the processing temperature may need to beabove the melting point of the CETP inhibitor and the polymer. Asmentioned above, alternatively, a liquid or low-melting point excipientmay be added that promotes melting or the mutual solubility of theconcentration-enhancing polymer and a CETP inhibitor. A high amount ofmechanical energy may also be needed to mix the CETP inhibitor and thepolymer to form a dispersion. Typically, the lowest processingtemperature and an extruder design that imparts the lowest amount ofmechanical energy, i.e., shear, that produces a satisfactory dispersion(substantially amorphous and substantially homogeneous) is chosen inorder to minimize the exposure of the CETP inhibitor to harshconditions.

[1162] Once the molten mixture of CETP inhibitor andconcentration-enhancing polymer is formed, the mixture should be rapidlysolidified to form the solid amorphous dispersion. By “rapidlysolidified” is meant that the molten mixture is solidified sufficientlyfast that substantial phase separation of the CETP inhibitor and polymerdoes not occur. Typically, this means that the mixture should besolidified in less than about 10 minutes, preferably less than about 5minutes and more preferably less than about 1 minute. If the mixture isnot rapidly solidified, phase separation can occur, resulting in theformation of CETP inhibitor-rich and polymer-rich phases.

[1163] Solidification often takes place primarily by cooling the moltenmixture to at least about 10° C. and preferably at least about 30° C.below it's melting point. As mentioned above, solidification can beadditionally promoted by evaporation of all or part of one or morevolatile excipients or solvents. To promote rapid cooling andevaporation of volatile excipients, the molten mixture is often formedinto a high surface area shape such as a rod or fiber or droplets. Forexample, the molten mixture can be forced through one or more smallholes to form long thin fibers or rods or may be fed to a device, suchas an atomizer such as a rotating disk, that breaks the molten mixtureup into droplets from 1 μm to 1 cm in diameter. The droplets are thencontacted with a relatively cool fluid such as air or nitrogen topromote cooling and evaporation.

[1164] A useful tool for evaluating and selecting conditions for formingsubstantially homogeneous, substantially amorphous dispersions via amelt-congeal or melt-extrusion process is the differential scanningcalorimeter (DSC). While the rate at which samples can be heated andcooled in a DSC is limited, it does allow for precise control of thethermal history of a sample. For example, the CETP inhibitor andconcentration-enhancing polymer may be dry-blended and then placed intothe DSC sample pan. The DSC can then be programmed to heat the sample atthe desired rate, hold the sample at the desired temperature for adesired time, and then rapidly cool the sample to ambient or lowertemperature. The sample can then be re-analyzed on the DSC to verifythat it was transformed into a substantially homogeneous, substantiallyamorphous dispersion (i.e., the sample has a single T_(g)). Using thisprocedure, the temperature and time required to achieve a substantiallyhomogeneous, substantially amorphous dispersion for a given CETPinhibitor and concentration-enhancing polymer can be determined.

[1165] Another method for forming solid amorphous dispersions is by“solvent processing,” which consists of dissolution of the CETPinhibitor and one or more polymers in a common solvent. “Common” heremeans that the solvent, which can be a mixture of compounds, willdissolve both the CETP inhibitor and the polymer(s). After both the CETPinhibitor and the polymer have been dissolved, the solvent is rapidlyremoved by evaporation or by mixing with a non-solvent. Exemplaryprocesses are spray-drying, spray-coating (pan-coating, fluidized bedcoating, etc.), and precipitation by rapid mixing of the polymer andCETP inhibitor solution with CO₂, water, or some other non-solvent.Preferably, removal of the solvent results in the formation of asubstantially homogeneous, solid amorphous dispersion. In suchdispersions, the CETP inhibitor is dispersed as homogeneously aspossible throughout the polymer and can be thought of as a solidsolution of CETP inhibitor dispersed in the polymer(s), wherein thesolid amorphous dispersion is thermodynamically stable, meaning that theconcentration of CETP inhibitor in the polymer is at or below itsequilibrium value, or it may be considered to be a supersaturated solidsolution where the CETP inhibitor concentration in theconcentration-enhancing polymer(s) is above its equilibrium value.

[1166] The solvent may be removed by spray-drying. The term“spray-drying” is used conventionally and broadly refers to processesinvolving breaking up liquid mixtures into small droplets (atomization)and rapidly removing solvent from the mixture in a spray-dryingapparatus where there is a strong driving force for evaporation ofsolvent from the droplets. Spray-drying processes and spray-dryingequipment are described generally in Perry's Chemical Engineers'Handbook, pages 20-54 to 20-57 (Sixth Edition 1984). More details onspray-drying processes and equipment are reviewed by Marshall,“Atomization and Spray-Drying,” 50 Chem. Eng. Prog. Monogr. Series 2(1954), and Masters, Spray Drying Handbook (Fourth Edition 1985). Thestrong driving force for solvent evaporation is generally provided bymaintaining the partial pressure of solvent in the spray-dryingapparatus well below the vapor pressure of the solvent at thetemperature of the drying droplets. This is accomplished by (1)maintaining the pressure in the spray-drying apparatus at a partialvacuum (e.g., 0.01 to 0.50 atm); or (2) mixing the liquid droplets witha warm drying gas; or (3) both (1) and (2). In addition, at least aportion of the heat required for evaporation of solvent may be providedby heating the spray solution.

[1167] Solvents suitable for spray-drying can be any organic compound inwhich the CETP inhibitor and polymer are mutually soluble. Preferably,the solvent is also volatile with a boiling point of 150° C. or less. Inaddition, the solvent should have relatively low toxicity and be removedfrom the solid amorphous dispersion to a level that is acceptableaccording to The International Committee on Harmonization (ICH)guidelines. Removal of solvent to this level may require a subsequentprocessing step such as tray-drying. Preferred solvents include alcoholssuch as methanol, ethanol, n-propanol, iso-propanol, and butanol;ketones such as acetone, methyl ethyl ketone and methyl iso-butylketone; esters such as ethyl acetate and propylacetate; and variousother solvents such as acetonitrile, methylene chloride, toluene, and1,1,1-trichloroethane. Lower volatility solvents such as dimethylacetamide or dimethylsulfoxide can also be used. Mixtures of solvents,such as 50% methanol and 50% acetone, can also be used, as can mixtureswith water, so long as the polymer and CETP inhibitor are sufficientlysoluble to make the spray-drying process practicable. Generally, due tothe hydrophobic nature of low-solubility CETP inhibitors, non-aqueoussolvents are preferred, meaning that the solvent comprises less thanabout 10 wt % water.

[1168] The solvent-bearing feed, comprising the CETP inhibitor and theconcentration-enhancing polymer, can be spray-dried under a wide varietyof conditions and yet still yield dispersions with acceptableproperties. For example, various types of nozzles can be used to atomizethe spray solution, thereby introducing the spray solution into thespray-dry chamber as a collection of small droplets. Essentially anytype of nozzle may be used to spray the solution as long as the dropletsthat are formed are sufficiently small that they dry sufficiently (dueto evaporation of solvent) that they do not stick to or coat thespray-drying chamber wall.

[1169] Although the maximum droplet size varies widely as a function ofthe size, shape and flow pattern within the spray-dryer, generallydroplets should be less than about 500 μm in diameter when they exit thenozzle. Examples of types of nozzles that may be used to form the solidamorphous dispersions include the two-fluid nozzle, the fountain-typenozzle, the flat fan-type nozzle, the pressure nozzle and the rotaryatomizer. In a preferred embodiment, a pressure nozzle is used, asdisclosed in detail in commonly assigned copending U.S. ProvisionalApplication No. 60/353,986, the disclosure of which is incorporatedherein by reference.

[1170] The spray solution can be delivered to the spray nozzle ornozzles at a wide range of temperatures and flow rates. Generally, thespray solution temperature can range anywhere from just above thesolvent's freezing point to about 20° C. above its ambient pressureboiling point (by pressurizing the solution) and in some cases evenhigher. Spray solution flow rates to the spray nozzle can vary over awide range depending on the type of nozzle, spray-dryer size andspray-dry conditions such as the inlet temperature and flow rate of thedrying gas. Generally, the energy for evaporation of solvent from thespray solution in a spray-drying process comes primarily from the dryinggas.

[1171] The drying gas can, in principle, be essentially any gas, but forsafety reasons and to minimize undesirable oxidation of the CETPinhibitor or other materials in the solid amorphous dispersion, an inertgas such as nitrogen, nitrogen-enriched air or argon is utilized. Thedrying gas is typically introduced into the drying chamber at atemperature between about 60° and about 300° C. and preferably betweenabout 80° and about 240° C.

[1172] The large surface-to-volume ratio of the droplets and the largedriving force for evaporation of solvent leads to rapid solidificationtimes for the droplets. Solidification times should be less than about20 seconds, preferably less than about 10 seconds, and more preferablyless than 1 second. This rapid solidification is often critical to theparticles maintaining a uniform, homogeneous dispersion instead ofseparating into CETP inhibitor-rich and polymer-rich phases. In apreferred embodiment, the height and volume of the spray-dryer areadjusted to provide sufficient time for the droplets to dry prior toimpinging on an internal surface of the spray-dryer, as described indetail in commonly assigned, copending U.S. Provisional Application No.60/354,080, incorporated herein by reference. As noted above, to getlarge enhancements in concentration and bioavailability it is oftennecessary to obtain as homogeneous a dispersion as possible.

[1173] Following solidification, the solid powder typically stays in thespray-drying chamber for about 5 to 60 seconds, further evaporatingsolvent from the solid powder. The final solvent content of the soliddispersion as it exits the dryer should be low, since this reduces themobility of the CETP inhibitor molecules in the solid amorphousdispersion, thereby improving its stability. Generally, the solventcontent of the solid amorphous dispersion as it leaves the spray-dryingchamber should be less than 10 wt % and preferably less than 2 wt %.Following formation, the solid amorphous dispersion can be dried toremove residual solvent using suitable drying processes, such as traydrying, fluid bed drying, microwave drying, belt drying, rotary drying,and other drying processes known in the art.

[1174] The solid amorphous dispersion is usually in the form of smallparticles. The mean size of the particles may be less than 500 μm indiameter, or less than 100 μm in diameter, less than 50 μm in diameteror less than 25 μm in diameter. When the solid amorphous dispersion isformed by spray-drying, the resulting dispersion is in the form of suchsmall particles. When the solid amorphous dispersion is formed by othermethods such as by melt-congeal or extrusion processes, the resultingsolid amorphous dispersion may be sieved, ground, or otherwise processedto yield a plurality of small particles.

[1175] Once the solid amorphous dispersion comprising the CETP inhibitorand concentration-enhancing polymer has been formed, several processingoperations can be used to facilitate incorporation of the solidamorphous dispersion into a dosage form. These processing operationsinclude drying, granulation, and milling.

[1176] The solid amorphous dispersion may be granulated to increaseparticle size and improve handling of the solid amorphous dispersionwhile forming a suitable dosage form. Preferably, the average size ofthe granules will range from 50 to 1000 μm. Such granulation processesmay be performed before or after the composition is dried, as describedabove. Dry or wet granulation processes can be used for this purpose. Anexample of a dry granulation process is roller compaction. Wetgranulation processes can include so-called low shear and high sheargranulation, as well as fluid bed granulation. In these processes, agranulation fluid is mixed with the composition after the dry componentshave been blended to aid in the formation of the granulated composition.Examples of granulation fluids include water, ethanol, isopropylalcohol, n-propanol, the various isomers of butanol, and mixturesthereof.

[1177] If a wet granulation process is used, the granulated compositionis often dried prior to further processing. Examples of suitable dryingprocesses to be used in connection with wet granulation are the same asthose described above. Where the solid amorphous dispersion is made by asolvent process, the composition can be granulated prior to removal ofresidual solvent. During the drying process, residual solvent andgranulation fluid are concurrently removed from the composition.

[1178] Once the composition has been granulated, it may then be milledto achieve the desired particle size. Examples of suitable processes formilling the composition include hammer milling, ball milling,fluid-energy milling, roller milling, cutting milling, and other millingprocesses known in the art.

[1179] Processes for forming solid amorphous dispersions of CETPinhibitors and concentration-enhancing polymers are described in detailin commonly assigned, copending U.S. patent application Ser. Nos.09/918,127 and 10/066,091, incorporated herein by reference.

HMG-CoA REDUCTASE INHIBITORS

[1180] The HMG-CoA reductase inhibitor may be any HMG-CoA reductaseinhibitor capable of lowering plasma concentrations of low-densitylipoprotein, total cholesterol, or both. The HMG-CoA reductase inhibitoris acid-sensitive, meaning that the drug either chemically reacts withor otherwise degrades in the presence of acidic species. Examples ofchemical reactions include hydrolysis, lactonization, ortransesterification in the presence of acidic species.

[1181] In one aspect, the HMG-CoA reductase inhibitor is from a class oftherapeutics commonly called statins. Examples of HMG-CoA reductaseinhibitors that may be used include but are not limited to lovastatin(MEVACOR®; see U.S. Pat. Nos. 4,231,938; 4,294,926; 4,319,039),simvastatin (ZOCOR®; see U.S. Pat. Nos. 4,444,784; 4,450,171, 4,820,850;4,916,239), pravastatin (PRAVACHOL®; see U.S. Pat. Nos. 4,346,227;4,537,859; 4,410,629; 5,030,447 and 5,180,589), lactones of pravastatin(see U.S. Pat. No. 4,448,979), fluvastatin (LESCOL®; see U.S. Pat. Nos.5,354,772; 4,911,165; 4,739,073; 4,929,437; 5,189,164; 5,118,853;5,290,946; 5,356,896), lactones of fluvastatin, atorvastatin (LIPITOR®;see U.S. Pat. Nos. 5,273,995; 4,681,893; 5,489,691; 5,342,952), lactonesof atorvastatin, cerivastatin (also known as rivastatin and BAYCHOL®;see U.S. Pat. No. 5,177,080 and European Application No. EP-491226A),lactones of cerivastatin, rosuvastatin (Crestor®; see U.S. Pat. Nos.5,260,440 and RE37314, and European Patent No. EP521471), lactones ofrosuvastatin, itavastatin, nisvastatin, visastatin, atavastatin,bervastatin, compactin, dihydrocompactin, dalvastatin, fluindostatin,pitivastatin, mevastatin (see U.S. Pat. No. 3,983,140), and velostatin(also referred to as synvinolin). Other examples of HMG-CoA reductaseinhibitors are described in U.S. Pat. Nos. 5,217,992; 5,196,440;5,189,180; 5,166,364; 5,157,134; 5,110,940; 5,106,992; 5,099,035;5,081,136; 5,049,696; 5,049,577; 5,025,017; 5,011,947; 5,010,105;4,970,221; 4,940,800; 4,866,058; 4,686,237; 4,647,576; EuropeanApplication Nos. 0142146A2 and 0221025A1; and PCT Application Nos. WO86/03488, WO 86/07054, and WO 97/06802. Also included arepharmaceutically acceptable forms of the above. All of the abovereferences are incorporated herein by reference. Preferably the HMG-CoAreductase inhibitor is selected from the group consisting offluvastatin, lovastatin, pravastatin, atorvastatin, simvastatin,cerivastatin, rivastatin, mevastatin, velostatin, compactin,dalvastatin, fluindostatin, rosuvastatin, pitivastatin,dihydrocompactin, and pharmaceutically acceptable forms thereof. By“pharmaceutically acceptable forms” is meant any pharmaceuticallyacceptable derivative or variation, including stereoisomers,stereoisomer mixtures, enantiomers, solvates, hydrates, isomorphs,polymorphs, salt forms and prodrugs.

[1182] A test to determine whether an HMG-CoA reductase inhibitor isacid sensitive is to administer the drug to an acidic aqueous solutionand plot drug concentration versus time. The acidic solution should havea pH of from 1-4. HMG-CoA reductase inhibitors that are acid sensitiveare those for which the drug concentration decreases by at least 1%within 24 hours of administration of the drug to the acidic solution. Ifthe drug concentration changes by 1% in the 6-24 hour time period, thenthe drug is “slightly acid-sensitive.” If the drug concentration changesby 1% in the 1-6 hour time period, then the drug is “moderatelyacid-sensitive.” If the drug concentration changes by 1% in less than 1hour, then the drug is “highly acid-sensitive.” The present inventionfinds increasing utility for HMG-CoA reductase inhibitors that areslightly acid-sensitive, moderately acid-sensitive and highlyacid-sensitive.

[1183] In one embodiment, the HMG-CoA reductase inhibitor is selectedfrom the group consisting of trans-6-[2-(3 or 4-carboxamido-substitutedpyrrol-1-yl)alkyl]-4-hydroxypyran-2-ones and corresponding pyranring-opened hydroxy acids derived therefrom. These compounds have beendescribed in U.S. Pat. No. 4,681,893, which is herewith incorporated byreference in the present specification. The pyran ring-opened hydroxyacids which are intermediates in the synthesis of the lactone compoundscan be used as free acids or as pharmaceutically acceptable metal oramine salts. In particular, these compounds can be represented by thefollowing structure:

[1184] wherein X is —CH₂-, —CH₂CH₂-, —CH₂CH₂CH₂- or —CH₂CH(CH₃)-; R₁ is1-naphthyl; 2-naphthyl; cyclohexyl, norbornenyl; 2-,3-, or 4-pyridinyl;phenyl; phenyl substituted with fluorine, chlorine, bromine, hydroxyl,trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of fromone to four carbon atoms, or alkanoylalkoxy of from two to eight carbonatoms; either R₂ or R₃ is —CONR₅R₆ where R₅ and R₆ are independentlyhydrogen; alkyl of from one to six carbon atoms; 2-,3-, or 4-pyridinyl;phenyl; phenyl substituted with fluorine, chlorine, bromine, cyano,trifluoromethyl, or carboalkoxy of from three to eight carbon atoms; andthe other of R₂ or R₃ is hydrogen; alkyl of from one to six carbonatoms; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; phenyl; orphenyl substituted with fluorine, chlorine, bromine, hydroxyl,trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of fromone to four carbon atoms, or alkanoyloxy of from two to eight carbonatoms; R₄ is alkyl of from one to six carbon atoms; cyclopropyl;cyclobutyl; cyclopentyl; cyclohexyl; or trifluoromethyl; and M is apharmaceutically acceptable salt (e.g., counter ion), which includes apharmaceutically acceptable metal salt or a pharmaceutically acceptableamine salt.

[1185] Among the stereo-specific isomers, one preferred HMG-CoAreductase inhibitor is atorvastatin trihydrate hemi-calcium salt. Thispreferred compound is the ring-opened form of(2R-trans)-5-(4-fluorophenyl)-2-(1methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide,namely, the enantiomer [R-(R*,R*)]-2-(4-fluorophenyl-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl)]-1H-pyrrole-1-heptanoicacid hemicalcium salt. Its chemical structure may be represented by thefollowing structure:

[1186] The specific isomer has been described in U.S. Pat. No.5,273,995, herein incorporated by reference. In a preferred embodiment,the HMG-CoA reductase inhibitor is selected from the group consisting ofatorvastatin, the cyclized lactone form of atorvastatin, a 2-hydroxy,3-hydroxy or 4-hydroxy derivative of such compounds, andpharmaceutically acceptable forms thereof.

[1187] In practice, use of the salt form amounts to use of the acid orlactone form. Appropriate pharmaceutically acceptable salts within thescope of the invention are those derived from bases such as sodiumhydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide,1-deoxy-2-(methylamino)-D-glucitol, magnesium hydroxide, zinc hydroxide,aluminum hydroxide, ferrous or ferric hydroxide, ammonium hydroxide ororganic amines such as N-methylglucamine, choline, arginine and thelike. Preferably, the lithium, calcium, magnesium, aluminum and ferrousor ferric salts are prepared from the sodium or potassium salt by addingthe appropriate reagent to a solution of the sodium or potassium salt,i.e., addition of calcium chloride to a solution of the sodium orpotassium salt of the compound of the formula A will give the calciumsalt thereof.

PREPARATION OF UNITARY DOSAGE FORMS

[1188] The unitary dosage form may be in the form of a tablet, caplet,pill, capsule, powder or other dosage form known in the art. The amountof CETP inhibitor and HMG-CoA reductase inhibitor present in the dosageform will vary depending on the desired dose for each compound, which inturn, depends on the potency of the compound and the condition beingtreated. For example, the desired dose for the CETP inhibitortorcetrapib, also known as[2R,4S]-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester, ranges from 1 mg/day to 1000 mg/day, preferably 10 to250 mg/day, more preferably 30 to 90 mg/day. For the HMG-CoA reductaseinhibitor atorvastatin calcium, the dose ranges from 1 to 160 mg/day,preferably 2 to 80 mg/day. For the HMG-CoA reductase inhibitorslovastatin, pravastatin sodium, simvastatin, rosuvastatin calcium, andfluvastatin sodium, the dose ranges from 2 to 160 mg/day, preferably 10to 80 mg/day. For the HMG-CoA reductase inhibitor cerivastatin sodium,the dose ranges from 0.05 to 1.2 mg/day, preferably 0.1 to 1.0 mg/day.

[1189] One method for forming the unitary dosage form is to first blendthe solid amorphous dispersion of the CETP inhibitor and neutral orneutralized concentration-enhancing polymer, the HMG-CoA reductaseinhibitor, and optional excipients using procedures well-known in theart. See for example, Remington: The Science and Practice of Pharmacy,20^(th) Edition (2000). Examples of blending equipment includetwin-shell blenders, fluidized beds, and V blenders.

[1190] Alternatively, the CETP inhibitor/polymer solid amorphousdispersion, HMG-CoA reductase inhibitor, and optional excipients, may begranulated. Exemplary methods for granulating the materials are wetgranulation and dry granulation, both well known in the art. Forexample, the solid amorphous dispersion, HMG-CoA reductase inhibitor,and optional excipients may be granulated by mechanical means by, forexample, roller compaction or “slugging,” followed by milling to formgranules. The granules typically have improved flow, handling, blending,and compression properties relative to the ungranulated materials. Wetgranulation techniques may also be employed, provided the solvents andprocess selected do not alter the properties of the solid amorphousdispersion. When wet granulation is used, the granulation liquid istypically removed from the granules during or after the granulationprocess. The so-formed granules typically have an average diameterranging from 50 μm to 1000 μm, preferably 50 μm to about 800 μm,although granules outside this range can be used. Improved wetting,disintegrating, dispersing and dissolution properties may be obtained bythe inclusion of other excipients described below.

[1191] Other conventional formulation excipients may be employed in thedosage form, including those excipients well known in the art, e.g., asdescribed in Remington: The Science and Practice of Pharmacy, 20^(th)Edition (2000). Generally, excipients such as surfactants, pH modifiers,disintegrants, porosigens, fillers, matrix materials, complexing agents,solubilizers, pigments, lubricants, glidants, flavorants, antioxidants,and so forth may be used for customary purposes and in typical amountswithout adversely affecting the properties of the compositions.

[1192] One very useful class of excipients is surfactants, preferablypresent from 0 to 10 wt %. Suitable surfactants include fatty acid andalkyl sulfonates; commercial surfactants such as benzalkonium chloride(HYAMINE® 1622 from Lonza, Inc. of Fairlawn, N.J.); dioctyl sodiumsulfosuccinate (DOCUSATE SODIUM from Mallinckrodt Specialty Chemicals ofSt. Louis, Miss.); polyoxyethylene sorbitan fatty acid esters (TWEEN®from ICI Americas Inc. of Wilmington, Dela.; LIPOSORB® O-20 fromLipochem Inc. of Patterson N.J.; CAPMUL® POE-0 from Abitec Corp. ofJanesville, Wis.); natural surfactants such as sodium taurocholic acid,1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, lecithin, and otherphospholipids and mono- and diglycerides; andpolyoxyethylene-polyoxypropylene. Such materials can advantageously beemployed to increase the rate of dissolution by, for example,facilitating wetting, or otherwise increase the rate of release of theCETP inhibitor and/or the HMG-CoA reductase inhibitor from the dosageform.

[1193] Inclusion of pH modifiers such as acids, bases, or buffers mayalso be beneficial in an amount of from 0 to 10 wt %. In a preferredembodiment, the unitary dosage form also includes a base. The inclusionof a base can locally raise the pH in the dosage form, leading to animprovement in chemical stability of the HMG-CoA reductase inhibitor.The term “base” is used broadly to include not only strong bases such assodium hydroxide, but also weak bases and buffers that are capable ofachieving the desired increase chemical stability. Examples of basesinclude hydroxides, such as sodium hydroxide, calcium hydroxide,ammonium hydroxide, and choline hydroxide; bicarbonates, such as sodiumbicarbonate, potassium bicarbonate, and ammonium bicarbonate;carbonates, such as ammonium carbonate, calcium carbonate, and sodiumcarbonate; amines, such as tris(hydroxymethyl)amino methane,ethanolamine, diethanolamine, N-methyl glucamine, glucosamine,ethylenediamine, N,N′-dibenzylethylenediamine,N-benzyl-2-phenethylamine, cyclohexylamine, cyclopentylamine,diethylamine, isopropylamine, diisopropylamine, dodecylamine, andtriethylamine; proteins, such as gelatin; amino acids such as lysine,arginine, guanine, glycine, and adenine; polymeric amines, such aspolyamino methacrylates, such as Eudragit E; conjugate bases of variousacids, such as sodium acetate, sodium benzoate, ammonium acetate,disodium phosphate, trisodium phosphate, calcium hydrogen phosphate,sodium phenolate, sodium sulfate, ammonium chloride, and ammoniumsulfate; salts of EDTA, such as tetra sodium EDTA; and salts of variousacidic polymers such as sodium starch glycolate, sodium carboxymethylcellulose and sodium polyacrylic acid. In one embodiment, the basepartially neutralizes the acidic concentration-enhancing polymer, aspreviously discussed; however, a base may also be included when thesolid amorphous dispersion comprises a CETP inhibitor and a neutralconcentration-enhancing polymer.

[1194] Examples of disintegrants include sodium starch glycolate, sodiumcarboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellosesodium, crospovidone, polyvinylpolypyrrolidone, methyl cellulose,microcrystalline cellulose, powdered cellulose, lower alkyl-substitutedhydroxypropyl cellulose, polacrilin potassium, starch, pregelatinizedstarch, sodium alginate, and mixtures thereof. Generally, thedisintegrant will comprise from 1 wt % to 25 wt %, preferably from 5 wt% to 20 wt % of the dosage form.

[1195] The unitary dosage form may also include a porosigen. A“porosigen” is a material that, when present in the formulationcontaining the solid amorphous dispersion, leads to a high porosity andhigh strength following compression of the blend into a tablet. Inaddition, preferred porosigens are soluble in an acidic environment withaqueous solubilities typically greater than 1 mg/mL at a pH less thanabout 4. Generally, the predominant deformation mechanism for porosigensunder compression is brittle fracture rather than plastic flow. Examplesof porosigens include acacia, calcium carbonate, calcium sulfate,calcium sulfate dihydrate, compressible sugar, dibasic calcium phosphate(anhydrous and dihydrate), tribasic calcium phosphate, monobasic sodiumphosphate, dibasic sodium phosphate, lactose, magnesium oxide, magnesiumcarbonate, silicon dioxide, magnesium aluminum silicate, maltodextrin,mannitol, methyl cellulose, microcrystalline cellulose, sorbitol,sucrose and xylitol. Of these, microcrystalline cellulose and both formsof dibasic calcium phosphate (anhydrous and dihydrate) are preferred.Generally, the porosigen will comprise from 5 to 70 wt %, and preferablyfrom 10 to 50 wt % of the dosage form.

[1196] Examples of other matrix materials, fillers, or diluents includedextrose, compressible sugar, hydrous lactose, corn starch, silicicanhydride, polysaccharides, dextrates, dextran, dextrin, dextrose,calcium carbonate, calcium sulfate, poloxamers, and polyethylene oxide.

[1197] Another optional excipient is a binder such as methyl cellulose,carboxymethylcellulose, hydroxypropylcellulose,hydroxymethylpropylcellulose, polyvinylpyrrolidone, polyvinylalcohol orstarch.

[1198] Examples of drug-complexing agents or solubilizers includepolyethylene glycols, caffeine, xanthene, gentisic acid andcylodextrins.

[1199] Examples of lubricants include calcium stearate, glycerylmonostearate, glyceryl palmitostearate, hydrogenated vegetable oil,light mineral oil, magnesium stearate, mineral oil, polyethylene glycol,sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearicacid, talc and zinc stearate.

[1200] Examples of glidants include silicon dioxide, talc andcornstarch.

[1201] Examples of antioxidants include butylated hydroxyanisole, sodiumascorbate, butylated hydroxytoluene, sodium metabisulfate, malic acid,citric acid and ascorbic acid.

[1202] In a preferred embodiment, the unitary dosage form comprises astabilizing agent for the HMG-CoA reductase inhibitor. The stabilizingagent stabilizes the HMG-CoA reductase inhibitor by reducing acidcatalyzed degradation. The stabilizing agent may be a basic inorganicpharmaceutically acceptable salt. Exemplary salts include: salts ofcalcium, such as calcium carbonate and calcium hydroxide; salts ofmagnesium, such as magnesium carbonate, magnesium hydroxide, magnesiumoxide, magnesium silicate, magnesium aluminate, and aluminum magnesiumhydroxide; salts of lithium, such as lithium hydroxide and similarlithium compounds; or, other similarly suitable salts of alkaline earthmetals. The basic inorganic salts of calcium, lithium or magnesium canbe utilized in a weight ratio ranging between about 0.1 to 1 and about50 to 1 of salt compound to HMG-CoA reductase inhibitor.

[1203] A preferred stabilizing agent is calcium carbonate. The inventorshave observed that the size of the calcium carbonate particles isrelated to the effectiveness of the calcium carbonate as a stabilizingagent, with smaller particle size resulting in better performance as astabilizing agent. Preferred grades of calcium carbonate areprecipitated grades of calcium carbonate having a particle size of lessthan about ten microns (μm). Exemplary grades of precipitated calciumcarbonate include Vicality Medium PCC and Vicality Heavy PCC availablefrom Specialty Minerals, Pre-carb 150 available from Mutchler, andPCC-250 available from Particle Dynamics.

[1204] The CETP inhibitor/polymer solid amorphous dispersion, HMG-CoAreductase inhibitor, and optional excipients may be blended orgranulated and then compressed to form the dosage form, such as tablets,caplets, or pills. The compressed dosage forms may be formed using anyof a wide variety of presses used in the fabrication of pharmaceuticaldosage forms. Examples include single-punch presses, rotary tabletpresses, and multilayer rotary tablet presses, all well-known in theart. See Remington: The Science and Practice of Pharmacy (20^(th)Edition, 2000). The compressed dosage form may be of any shape,including round, oval, oblong, cylindrical, or triangular. The upper andlower surfaces of the compressed dosage form may be flat, round,concave, or convex.

[1205] When formed by compression, the dosage form preferably has a“strength” of at least 5 Kiloponds (Kp)/cm², and more preferably atleast 7 Kp/cm². Here, “strength” is the fracture force, also known asthe tablet “hardness,” required to fracture a tablet formed from thematerials, divided by the maximum cross-sectional area of the tabletnormal to that force. The fracture force may be measured using aSchleuniger Tablet Hardness Tester, model 6D. To achieve the desiredstrength, the blend of the CETP inhibitor/polymer solid amorphousdispersion, HMG-CoA reductase inhibitor, and optional excipients shouldbe compressed with sufficient force while forming the dosage form. Thecompression force required to achieve this strength will depend on thesize of the tablet, but generally will be greater than about 5 kP/cm².Friability is a well-known measure of a dosage form's resistance tosurface abrasion that measures weight loss in percentage aftersubjecting the dosage form to a standardized agitation procedure.Friability values of from 0.8 to 1.0% are regarded as constituting theupper limit of acceptability. Dosage forms having a strength of greaterthan 5 kP/cm² generally are very robust, having a friability of lessthan 0.5%, preferably less than 0.1%.

[1206] Alternatively, the CETP inhibitor/polymer solid amorphousdispersion, HMG-CoA reductase inhibitor, and optional excipientsdescribed above may be filled into a capsule, such as a hard- orsoft-gelatin capsule or a capsule made from some other material, e.g.,starch, to form the unitary dosage form. Such capsules are well known inthe art (see, for example, Remington: The Science and Practice ofPharmacy (20^(th) Edition, 2000)).

[1207] Yet another embodiment of the unitary dosage form is a powderform. The powder dosage form can then be taken dry or mixed with aliquid to form a paste, suspension or slurry prior to dosing. An exampleof this type of dosage form is a sachet, sometimes known in the art asan oral powder for constitution (OPC). The CETP inhibitor/polymer solidamorphous dispersion, the HMG-CoA reductase inhibitor, and optionalexcipients may be mixed and placed into a suitable container, such as apouch, bottle, box, bag, or other container known in the art.

[1208] In another embodiment, the unitary dosage form comprises (a) aCETP inhibitor composition, the CETP inhibitor composition comprising asolid amorphous dispersion of a CETP inhibitor and a neutral orneutralized concentration-enhancing polymer; and (b) an HMG-CoAreductase inhibitor composition comprising an HMG-CoA reductaseinhibitor. The CETP inhibitor composition and the HMG-CoA reductaseinhibitor composition are combined such that the solid amorphousdispersion and the HMG-CoA reductase inhibitor are substantiallyseparate from one another in the dosage form.

[1209] The HMG-CoA reductase composition may comprise a stabilizingmetal or alkaline earth metal salt, additional excipients which areknown as suitable agents in the art comprising combinations andconcentrations as further described below. In a preferred embodiment,the HMG-CoA reductase composition contains conventional additionalmaterials suitable for forming a tablet. Such excipients include adiluent, binder, and disintegrant. Antioxidants can also be incorporatedinto the HMG-CoA reductase inhibitor composition to prevent anyoxidation of the drug compound. For example, antioxidants that could beused are butylated hydroxyanisole, sodium ascorbate, butylatedhydroxytoluene, sodium metabisulfate, malic acid, citric acid andascorbic acid.

[1210] In one HMG-CoA reductase inhibitor composition, the compositioncomprises a stabilizing agent, diluents, disintegrant, and surfactant.The basic excipient, calcium carbonate, has been found to chemicallystabilize HMG-CoA reductase inhibitors, such as atorvastatin calcium.Microcrystalline cellulose and hydrous lactose are applied as suitablediluents. Croscarmellose sodium is present as a disintegrant. Thenon-ionic detergent Tween 80 is used as a surfactant. The compositionalso contains hydroxypropyl cellulose as binder selected from amongseveral applicable substances such as, i.e., polyethylene glycol,polyvinylpyrrolidone, polyvinyl alcohol, hydroxymethylcellulose orhydroxypropylmethylcellulose. As anti-oxidants, reagents such asbutylated hydroxyanisole, sodium ascorbate, ascorbic acid or others mayoptionally be incorporated in the composition. Magnesium stearate can beselected from a group including other substances such as stearic acid,palmitic acid, talc or similar lubricating compounds.

[1211] Other possible and supplemental ingredients such aspreservatives, dryers, glidants, or colorants known as conventional bythose skilled in the art may be included optionally in the HMG-CoAreductase inhibitor composition.

[1212] In one aspect, the HMG-CoA reductase inhibitor compositioncomprises the following concentration ranges of ingredients by weight:the HMG-CoA reductase inhibitor is in the range from about 1% to about50%; calcium carbonate from about 5% to about 75%; microcrystallinecellulose from about 5% to about 75%; hydrous lactose from about 1% toabout 80%; croscarmellose sodium from about 1% to about 15%;hydroxypropylcellulose from about 0.5% to about 6%; Tween 80 from about0.1% to about 4%; magnesium stearate from about 0.25% to about 2%; andsodium ascorbate from about 0.0% to about 3%.

[1213] A more preferred HMG-CoA reductase inhibitor compositioncomprises the following approximate concentrations of ingredients byweight: about 13.9 wt % of the HMG-CoA reductase inhibitor atorvastatinhemicacium trihydrate; about 42.4 wt % of calcium carbonate; about 17.7wt % microcrystalline cellulose; about 19.2 wt % pregelatanized starch;about 2.5 wt % hydroxypropyl cellulose; and about 0.5 wt % Tween 80.

[1214] The HMG-CoA reductase inhibitor composition may be formed by anyconventional method for combining the HMG-CoA reductase inhibitor andexcipients. Exemplary methods include wet and dry granulation. If wetgranulation is used, a stabilizing agent such as calcium carbonate ispreferably included to keep chemical degradation of the HMG-CoAreductase inhibitor at an acceptable level.

[1215] One exemplary method for forming the HMG-CoA reductase inhibitorcomposition comprises (a) milling an excess of the drug, (b) dissolvingat least one binder additive in aqueous surfactant solution; (c)blending the milled drug with at least one drug-stabilizing additive andat least one diluent additive with the drug-stabilizing additive and onehalf of a disintegrant additive in a rotary mixing vessel equipped witha chopping device; (d) granulating the blended drug ingredient mixtureof step (c) with the surfactant/binder solution of step (b) in gradualincrements in the chopper equipped mixing vessel; (e) drying thegranulated drug mixture overnight at about 50° C.; (f) sieving the driedgranulated drug mixture; (g) tumble blending the sieved drug mixturewith the remaining amount of the disintegrant additive; (h) mixingseparately an aliquot of the drug mixture of step (g) with magnesiumstearate, sieving same, and returning same to the drug mixture of step(g) and tumble blending the entire drug mixture.

[1216] In one embodiment, the CETP inhibitor composition and HMG-CoAreductase inhibitor composition are blended together and then compressedto form a tablet, caplet, pill, or other dosage forms formed bycompression forces known in the art. In another embodiment, the CETPinhibitor composition and the HMG-CoA reductase inhibitor compositionare blended together and filled into a capsule. In another embodiment,the CETP inhibitor composition and the HMG-CoA reductase inhibitorcomposition are blended together to form a powder dosage form. Inanother embodiment, the unitary dosage form is in the form of a kitcomprising the CETP inhibitor composition and the HMG-CoA reductaseinhibitor composition. The kit is designed such that the HMG-CoAreductase inhibitor and the solid amorphous dispersion are substantiallyseparate.

[1217] Yet another embodiment of the unitary dosage form is a kitcomprising two separate compositions: (1) one containing the solidamorphous dispersion comprising a CETP inhibitor and an acidicconcentration-enhancing polymer, and (2) one containing the HMG-CoAreductase inhibitor. The kit is designed such that the HMG-CoA reductaseinhibitor and the solid amorphous dispersion are substantially separate.The kit includes means for containing the separate compositions such asa divided bottle or a divided foil packet; however, the separatecompositions may also be contained within a single, undivided container.Typically the kit includes directions for the administration of theseparate components.

[1218] Further details of such unitary dosage forms are given incommonly assigned Provisional Patent Application No. 60/435,298,entitled “Dosage Forms Comprising a CETP Inhibitor and an HMG-CoAReductase Inhibitor,” filed Dec. 20, 2002, the entire disclosure ofwhich is herein incorporated by reference.

COATINGS

[1219] The unitary dosage form may optionally be coated with aconventional coating well known in the art. The coatings may be used tomask taste, improve appearance, facilitate swallowing of the dosageform, or to delay, sustain or otherwise control the release of the drugfrom the dosage form. Such coatings may be fabricated by anyconventional means including fluidized bed coating, spray-coating,pan-coating and powder-coating using aqueous or organic solvents.Examples of suitable coating materials include sucrose, maltitol,cellulose acetate, ethyl cellulose, methylcellulose, sodiumcarboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, polymethacrylates,polyacrylates, polyvinyl alcohol, polyvinyl pyrrolidone, cetyl alcohol,gelatin, maltodextrin, paraffin wax, microcrystalline wax, and Carnaubawax. Mixtures of polymers may also be used. Preferred coatings includethe commercial aqueous coating formulations Surelease® and Opadry®available from Colorcon Inc. (West Point, Pa.). Another exemplarycommercial coating is Lustre Clear® from FMC Corp., located inPhiladelphia, Pa.

[1220] In some cases, to avoid poor toleration or to avoid degradation,it is desired that drugs in the unitary dosage form not be released inthe stomach. In these instances, the dosage form may also be overcoatedwith one or more pH-sensitive coating compositions, commonly referred toin the pharmaceutical arts as “enteric” coatings, by conventionalprocedures in order to delay the release of drug until it reaches theduodenum or small intestine. pH-sensitive polymers suitable as entericcoatings include those which are relatively insoluble and impermeable atthe pH of the stomach, but which are more soluble or disintegrable orpermeable at the pH of the duodenum and small intestine. SuchpH-sensitive polymers include polyacrylamides, phthalate derivativessuch as acid phthalate of carbohydrates, amylose acetate phthalate,cellulose acetate phthalate (CAP), other cellulose ester phthalates,cellulose ether phthalates, hydroxypropylcellulose phthalate (HPCP),hydroxypropyl ethylcellulose phthalate (HPECP), hydroxypropylmethylcellulose phthalate (HPMCP), HPMCAS, methylcellulose phthalate(MCP), polyvinyl acetate phthalate (PVAcP), polyvinyl acetate hydrogenphthalate, sodium CAP, starch acid phthalate, cellulose acetatetrimellitate (CAT), styrene-maleic acid dibutyl phthalate copolymer,styrene-maleic acid/polyvinylacetate phthalate copolymer, styrene andmaleic acid copolymers, polyacrylic acid derivatives such as acrylicacid and acrylic ester copolymers, polymethacrylic acid and estersthereof, polyacrylic and methacrylic acid copolymers, shellac andcopolymers of vinyl acetate and crotonic acid.

[1221] A preferred group of pH-sensitive polymers includes CAP, PVAcP,HPMCP, HPMCAS, anionic acrylic copolymers of methacrylic acid andmethylmethacrylate, and copolymers of acrylic acid and at least oneacrylic acid ester.

[1222] To apply the pH-sensitive coating to the tablets, thepH-sensitive polymer is first dissolved in a suitable solvent to form acoating solution. Useful solvents for this purpose include ketones, suchas acetone; alcohols, such as methanol, ethanol, isopropyl alcohol,n-propyl alcohol, and the various isomers of butanol; chlorinatedhydrocarbons, such as methylene chloride; water; and mixtures of thesesolvents. The polymer may also be suspended in the solvent. The coatingsolution may also comprise a latex of the pH-sensitive polymer suspendedin an aqueous solution.

[1223] The coating solution may also contain one or more plasticizers,such as polyethylene glycols, triethyl citrate, propylene glycols,diethyl phthalate, dibutyl phthalate, castor oil, triacetin and othersknown in the art. The coating solution may also contain one or moreemulsifiers, such as polysorbate-80. Coating is conducted inconventional fashion, typically by dipping, spray-coating, orpan-coating.

[1224] Where the coating is an acidic polymer, it may be desired tofurther protect the HMG-CoA reductase inhibitor from degradation fromthe coating material. In such instances, it may be desired to provide aninner coating surrounding the HMG-CoA reductase inhibitor compositiononto which the exterior acidic coating may be applied. Otherconventional techniques may be used to prevent the coating fromdegrading the HMG-CoA reductase inhibitor.

[1225] The coating solution may also contain a base or buffer, such asthose discussed above. Use of a base or buffer will ensure the pH of thecoating solution is not so low as to increase chemical degradation ofthe HMG-CoA reductase inhibitor. Use of a base or buffer may also beused to minimize reaction of the coating formulation with otherexcipients in the dosage form.

[1226] The unitary dosage forms of the present invention may be used totreat any condition, which is subject to treatment by administering aCETP inhibitor and an HMG-CoA reductase inhibitor, as disclosed incommonly assigned, copending U.S. Patent Application No. 2002/0035125A1,the disclosure of which is herein incorporated by reference.

[1227] In one aspect, the unitary dosage forms of the present inventionare used for antiatheroscierotic treatment.

[1228] In another aspect, the unitary dosage forms of the presentinvention are used for slowing and/or arresting the progression ofatherosclerotic plaques.

[1229] In another aspect, the unitary dosage forms of the presentinvention are used for slowing the progression of atheroscleroticplaques in coronary arteries.

[1230] In another aspect, the unitary dosage forms of the presentinvention are used for slowing the progression of atheroscleroticplaques in carotid arteries.

[1231] In another aspect, the unitary dosage forms of the presentinvention are used for slowing the progression of atheroscleroticplaques in the peripheral arterial system.

[1232] In another aspect, the unitary dosage forms of the presentinvention, when used for treatment of atherosclerosis, causes theregression of atherosclerotic plaques.

[1233] In another aspect, the unitary dosage forms of the presentinvention are used for regression of atherosclerotic plaques in coronaryarteries.

[1234] In another aspect, the unitary dosage forms of the presentinvention are used for regression of atherosclerotic plaques in carotidarteries.

[1235] In another aspect, the unitary dosage forms of the presentinvention are used for regression of atherosclerotic plaques in theperipheral arterial system.

[1236] In another aspect, the unitary dosage forms of the presentinvention are used for HDL elevation treatment and antihyperlipidemictreatment (including LDL lowering).

[1237] In another aspect, the unitary dosage forms of the presentinvention are used for antianginal treatment.

[1238] In another aspect, the unitary dosage forms of the presentinvention are used for cardiac risk management.

[1239] Other features and embodiments of the invention will becomeapparent from the following examples, which are given for illustrationof the invention, rather than for limiting its intended scope.

EXAMPLES Example 1

[1240] Crystalline atorvastatin calcium was combined with a solidamorphous dispersion containing a CETP inhibitor and a neutralizedacidic polymer, and stored at 50° C. and 75% relative humidity for 3weeks. The stability of atorvastatin was improved relative to a controlcomposition containing an acidic polymer.

[1241] The following process was used to form a solid amorphousdispersion containing 25 wt % of the CETP inhibitor torcetrapib, alsoknown as[2R,4S]-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester, (torcetrapib) and 75 wt % hydroxypropylmethylcellulose acetate succinate (HPMCAS)(MF grade, available from Shin Etsu,located in Tokyo, Japan) wherein greater than 95% of the acidicsuccinate substituents had been neutralized with potassium hydroxide.First, a spray solution was formed containing 1500 mg HPMCAS (an acidicpolymer) in 45 g methanol with 82.3 mg potassium hydroxide (a sufficientamount to completely neutralize the acidic groups on the polymer). Next,500 mg torcetrapib and about 3 mL water were dissolved therein. Thesolution was pumped into a “mini” spray-drying apparatus via a ColeParmer 74900 series rate-controlling syringe pump at a rate of 1.3mL/min. The solution was sprayed using a Spraying Systems Co. two-fluidnozzle, model number SU1A, with nitrogen as the atomizing gas. Thenitrogen was pressurized and heated to a temperature of 70° C. at a flowrate of 1.0 scfm. The solution was sprayed from the top of an 11-cmdiameter stainless steel chamber. The resulting solid amorphousdispersion was collected on Whatman® filter paper, dried under vacuum,and stored in a dessicator. After drying, the solid amorphous dispersioncontained 25 wt % torcetrapib and 75 wt % neutralized HPMCAS-MF.

[1242] The spray-dried solid amorphous dispersion was evaluated in an invitro dissolution test using a microcentrifuge method. In this test, 7.2mg of the spray-dried solid amorphous dispersion was placed into amicrocentrifuge tube. The tube was placed in a 37° C. sonicating bath,and 1.8 mL phosphate buffered saline (PBS) at pH 6.5 and 290 mOsm/kg wasadded, resulting in a torcetrapib concentration of 1000 μg/mL if all ofthe drug had dissolved. The sample was quickly mixed using a vortexmixer for about 60 seconds. The sample was centrifuged at 13,000 G at37° C. for 1 minute. The resulting supernatant solution was then sampledand diluted 1:6 (by volume with methanol and then analyzed byhigh-performance liquid chromatography (HPLC). The contents of the tubewas mixed on the vortex mixer and allowed to stand undisturbed at 37° C.until the next sample was taken. Samples were collected at 4, 10, 20,40, 90, and 1200 minutes. The concentrations of drug obtained in thesesamples are shown in Table 1, which represent the average of duplicatetests.

[1243] As a control, an in vitro dissolution test was performed usingthe procedures described above except that 1.8 mg of crystalline drugwas used. The concentrations of drug obtained in in vitro dissolutiontests are shown in Table 1. TABLE 1 Torcetrapib Time Concentration AUCSample (min) (μg/mL) (min-μg/mL) Solid 0 0 0 Amorphous 4 190 400Dispersion 10 189 1500 using the 20 165 3300 neutralized 40 154 6500HPMCAS- 90 119 13,300 MG/K⁺ 1200 17 88,800 Crystalline Drug 0 0 0 4 <1<2 10 <1 <8 20 <1 <18 40 <1 <38 90 <1 <88 1200 <1 <1,200

[1244] The results of these dissolution tests are summarized in Table 2,which shows the maximum concentration of torcetrapib in solution duringthe first 90 minutes of the test (C_(max,90)), the area under theaqueous concentration versus time curve after 90 minutes (AUC₉₀), andthe concentration at 1200minutes (C₁₂₀₀). TABLE 2 Torcetrapib Conc.Concentration- in the Re- AUC90 Enhancing Dispersion ceptor C_(max,90)(min- Sample Polymer (wt %) Solution (μg/mL) μg/mL) Solid HPMCAS-MG 25PBS 190 13,300 Amorphous Neutralized Dispersion with K⁺ Crystalline NoneNA PBS <1 <88 Drug

[1245] The results summarized in Table 2 show that the solid amorphousdispersion provided concentration enhancement relative to crystallinedrug. The solid amorphous dispersion provided a C_(max,90) value thatwas greater than 1 90-fold that of the crystalline drug, and an AUC₉₀value that was greater than 151-fold that of the crystalline drug.

[1246] Example 1 consisted of a mixture of crystalline atorvastatin(14.3 wt %) and the CETP inhibitor dispersion with neutralized polymer(85.7 wt %). To form the mixture of Example 1, 42.9 mg of crystallineatorvastatin and 257.1 mg of the solid amorphous dispersion werecombined and blended for 20 minutes using a Turbula mixer. The mixturewas slugged using a Carver press at 500 psi, and then milled using amortar and pestle. The granules were screened using a #20 sieve.

[1247] Control 1 consisted of a mixture of crystalline atorvastatin(14.3 wt %) and the CETP inhibitor dispersion with un-neutralized acidicpolymer (85.7 wt %). The solid amorphous dispersion for Control 1 wasmade by forming a spray solution containing 25 g torcetrapib, 75 gHPMCAS (MG grade, available from Shin Etsu, located in Tokyo, Japan),and 900 g acetone. The spray solution was pumped using a high-pressurepump (Zenith Z-Drive 2000 High-Pressure Gear Pump) to a spray drier(Niro type XP Portable Spray-Dryer with a Liquid-Feed Process Vessel[PSD-1]) equipped with a pressure atomizer (Spraying Systems PressureNozzle and Body (SK 79-16)). The PSD-1 was equipped with a 9-inchchamber extension. The spray drier was also equipped with a diffuserplate having a 1% open area. The nozzle sat flush with the diffuserplate during operation. The spray solution was pumped to the spray drierat about 185 g/min, with an atomization pressure of about 280 psi.Drying gas (nitrogen) was circulated through the diffuser plate at aninlet temperature of about 98° C. The evaporated solvent and wet dryinggas exited the spray drier at a temperature of about 29° C. Thespray-dried solid amorphous dispersion formed by this process wascollected in a cyclone, and had a bulk specific volume of 4.5 cm³/gm.The solid amorphous dispersion was post-dried using a Gruenbergsingle-pass convection tray dryer operating at 40° C. for about 16hours. To form the mixture of Control 1, 42.9 mg of crystallineatorvastatin and 257.1 mg of the torcetrapid solid amoprhous dispersionwith un-neutralized polymer were combined, then blended, slugged,milled, and sieved as described for Example 1.

[1248] Example 1 and Control 1 were stored at 50° C. and 75% relativehumidity for 3 weeks to increase the rate of chemical and physicalchanges occurring in the materials in order to simulate a longer storageinterval in a typical storage environment. Following storage, sampleswere analyzed for atorvastatin purity using HPLC. To analyze the samplesby HPLC, about 0.4 mg/mL atorvastatin in the mixture was added to adissolving solvent. The dissolving solvent was made by combining 150 mLs50 mM ammonium acetate (pH 7.0), 600 mLs acetonitrile, and 250 mLsmethanol. Mobile phase A was made by adding 3 mLs acetic acid to 530 mLswater, adjusting to pH 4.0 with ammonium hydroxide, then adding 270 mLsacetonitrile and 200 mLs tetrahydrofuran. Mobile phase B was made byadding 1 mL acetic acid to 100 mLs water, adding half of the amount ofammonium hydroxide used to adjust Mobile phase A, then adding 700 mLsacetonitrile and 200 mLs tetrahydrofuran. The samples were analyzedusing a Waters Spherisorb ODS2 column, with a solvent flow rate of 1.5mL/min. Table 3 shows the solvent gradient used. TABLE 3 Time % A % B 0100 0 15 100 0 35 0 100 50 0 100 51 100 0 60 100 0

[1249] The UV absorbance of atorvastatin and atorvastatin impuritieswere measured at a wavelength of 244 nm. The atorvastatin lactoneimpurity eluting after about 10 minutes was chosen as the basis forcomparison. All peak areas were added and the lactone impurity aspercent of total peak area was calculated to give the degree ofdegradation. Results are shown below in Table 4. TABLE 4 Degree ofDegradation Sample (wt %) Example 1 0.06 Control 1 0.49

[1250] The results from Table 4 show that the atorvastatin in the sampleof Control 1 (atorvastatin mixed with the CETPI/un-neutralized acidicpolymer dispersion) contained 0.49 wt % lactone impurity. Example 1shows that a composition containing a CETP inhibitor solid amorphousdispersion comprising a neutralized acidic polymer provided improvedstability of atorvastatin relative to a composition containing adispersion comprising an acidic polymer.

[1251] A relative degree of improvement in chemical stability wasdetermined by taking the ratio of the degree of degradation of the drugin the control composition and the degree of degradation of the drug inthe composition of Example 1. For Example 1, where the degree ofdegradation of atorvastatin is 0.06 wt %, and the degree of degradationof Control 1 is 0.49 wt %, the relative degree of improvement is 0.49 wt%/0.06 wt %, or 8.17.

Example 2

[1252] Crystalline atorvastatin was combined with an amorphousdispersion containing a CETP inhibitor and a neutral polymer, and storedat 50° C. and 75% relative humidity for 3 weeks. The stability ofatorvastatin was improved relative to a control composition containingan acidic polymer.

[1253] The following process was used to form a solid amorphousdispersion containing 25 wt % torcetrapib and 75 wt % of the neutralpolymer hydroxypropyl methyl cellulose (HPMC). First, a spray solutionwas formed containing 1500 mg HPMC (E3 Prem Methocel® obtained from DowChemical Co., Midland, Mich.) in 48 g methanol. Next, 500 mg torcetrapiband about 2 mLs water were added. The solution was pumped into a “mini”spray-drying apparatus and spray-dried as described for Example 1. Afterdrying, the resulting amorphous dispersion contained 25 wt % torcetrapiband 75 wt % HPMC.

[1254] The spray-dried solid amorphous dispersion was evaluated in an invitro dissolution test using a microcentrifuge method as described inExample 1. The concentrations of drug obtained in these samples areshown in Table 5, which represent the average of duplicate tests. TABLE5 Torcetrapib Time Concentration AUC Sample (min) (μg/mL) (min-μg/mL)Solid 0 0 0 Amorphous 4 87 200 Dispersion 10 21 500 using the 20 12 700neutral polymer 40 9 900 HPMC 90 11 1400 1200 5 10,100

[1255] The results of these dissolution tests are summarized in Table 6,which shows the maximum concentration of torcetrapib in solution duringthe first 90 minutes of the test (C_(max,)90), the area under theaqueous concentration versus time curve after 90 minutes (AUC₉₀), andthe concentration at 1200 minutes (C₁₂₀₀). The results for thecrystalline drug are included for comparison. TABLE 6 Torcetrapib Conc.Concentration- in the Re- AUC90 Enhancing Dispersion ceptor C_(max,90)(min- Sample Polymer (wt %) Solution (μg/mL) μg/mL) Solid HPMC 25 PBS 871,400 Amorphous Dispersion Crystalline None NA PBS <1 <88 Drug

[1256] The results summarized in Table 6 show that the solid amorphousdispersion provided concentration enhancement relative to crystallinedrug. The solid amorphous dispersion provided a C_(max,90) value thatwas greater than 87-fold that of the crystalline drug, and an AUC₉₀value that was greater than 15-fold that of the crystalline drug.

[1257] Example 2 consisted of a mixture of crystalline atorvastatin(14.3 wt %) and the CETP inhibitor dispersion with neutral polymer (85.7wt %). To form the mixture of Example 2, 42.9 mg of crystallineatorvastatin and 257.1 mg of the solid amorphous dispersion above werecombined, then blended, slugged, milled, and sieved as described forExample 1.

[1258] Example 2 was stored at 50° C. and 75% relative humidity for 3weeks, then analyzed for atorvastatin purity using HPLC, as describedfor Example 1 and Control 1. All impurity peak areas were added and thelactone impurity as percent of total peak area was calculated to givethe degree of degradation. Results are shown below in Table 7. Control 1is shown again for comparison. TABLE 7 Degree of Degradation Sample (wt%) Example 2 0.13 Control 1 0.49

[1259] The atorvastatin in the sample of Example 2 contained 0.13 wt %lactone impurity after storage. The atorvastatin in the sample ofControl 1 (atorvastatin mixed with the CETP inhibitor/HPMCAS dispersion)contained 0.49 wt % lactone impurity after storage. Example 2 shows thatuse of a CETP inhibitor dispersion comprising a neutral polymer providedimproved atorvastatin stability relative to a composition comprising adispersion containing an acidic polymer. For Example 2, where the degreeof degradation of atorvastatin was 0.13 wt %, and the degree ofdegradation of Control 1 was 0.49 wt %, the relative degree ofimprovement was 0.49 wt %/0. 13 wt %, or 3.8.

Example 3

[1260] This example demonstrates neutralizing an acidicconcentration-enhancing polymer by adding base following formation ofthe solid amorphous dispersion.

[1261] Example 3 consisted of a mixture of crystalline atorvastatin(13.9 wt %), magnesium oxide (3.0 wt %), and the CETP inhibitordispersion with acidic polymer HPMCAS described for Control 1 (83.1 wt%). To form the mixture of Example 3, 42.9 mg of crystallineatorvastatin, 9.4 mg of magnesium oxide, and 257.1 mg of the solidamorphous dispersion containing 25 wt % torcetrapib and 75 wt % HPMCASwere combined, then blended, slugged, milled, and sieved as describedfor Example 1. Example 3 was stored at 50° C. and 75% relative humidityfor 3 weeks, then analyzed for atorvastatin purity using HPLC, asdescribed for Example 1 and Control 1. Results are shown below in Table8. TABLE 8 Degree of Degradation Sample (wt %) Example 3 0.19 Control 10.49

[1262] The results from Table 8 show that the atorvastatin in the sampleof Example 3 contains 0.19 wt % lactone impurity. The relative degree ofimprovement for Example 3 is 2.6 relative to Control 1.

[1263] The terms and expressions which have been employed in theforegoing specification are used therein as terms of description and notof limitation, and there is no intention, in the use of such terms andexpressions, of excluding equivalents of the features shown anddescribed or portions thereof, it being recognized that the scope of theinvention is defined and limited only by the claims which follow.

1. A unitary dosage form comprising: (a) a solid amorphous dispersioncomprising a cholesteryl ester transfer protein inhibitor and aconcentration-enhancing polymer; and (b) an HMG-CoA reductase inhibitor;wherein said concentration-enhancing polymer is at least one of aneutral polymer and a neutralized acidic polymer.
 2. The unitary dosageform of claim 1 wherein said concentration-enhancing polymer is saidneutral polymer.
 3. The unitary dosage form of claim 2 wherein saidunitary dosage form provides improved chemical stability of said HMG-CoAreductase inhibitor relative to a control dosage form identical theretoexcept that the concentration-enhancing polymer is hydroxypropyl methylcellulose acetate succinate.
 4. The unitary dosage form of claim 3wherein said dosage form provides a relative degree of improvement instability for said HMG-CoA reductase inhibitor of at least 1.25-foldrelative to said control dosage form.
 5. The unitary dosage form ofclaim 2 wherein said concentration-enhancing polymer is selected fromthe group consisting of hydroxypropyl methyl cellulose acetate,hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl methyl cellulose, hydroxyethyl celluloseacetate, hydroxyethyl ethyl cellulose, and mixtures thereof.
 6. Theunitary dosage form of claim 2 wherein said concentration-enhancingpolymer is selected from the group consisting of vinyl polymers andcopolymers having one or more substituents selected from the groupconsisting of hydroxyl-containing repeat units, alkylacyloxy-containingrepeat units, or cyclicamido-containing repeat units, polyvinyl alcoholsthat have at least a portion of their repeat units in the unhydrolyzedform, polyvinyl alcohol polyvinyl acetate copolymers, polyethyleneglycol, polyethylene glycol polypropylene glycol copolymers, polyvinylpyrrolidone, polyethylene polyvinyl alcohol copolymers,polyoxyethylene-polyoxypropylene block copolymers, and mixtures thereof.7. The unitary dosage form of claim 2 further comprising an excipientselected from the group consisting of a base and a buffer.
 8. Theunitary dosage form of claim 1 wherein said concentration-enhancingpolymer is said neutralized acidic polymer.
 9. The unitary dosage formof claim 8 wherein said unitary dosage form provides improved chemicalstability of said HMG CoA reductase inhibitor relative to a controldosage form identical thereto except that the concentration-enhancingpolymer is the unneutralized form of said neutralized acidic polymer.10. The unitary dosage form of claim 9 wherein said dosage form providesa relative degree of improvement in stability for said HMG-CoA reductaseinhibitor of at least 1.25-fold relative to said control dosage form.11. The unitary dosage form of claim 8 wherein said neutralized acidicpolymer has a degree of neutralization of at least 0.1%.
 12. The unitarydosage form of claim 8 wherein said neutralized acidic polymer is aneutralized form of a polymer selected from the group consisting ofhydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methylcellulose succinate, hydroxypropyl cellulose acetate succinate,hydroxyethyl methyl cellulose succinate, hydroxyethyl cellulose acetatesuccinate, hydroxypropyl methyl cellulose phthalate, hydroxyethyl methylcellulose acetate succinate, hydroxyethyl methyl cellulose acetatephthalate, cellulose acetate phthalate, methyl cellulose acetatephthalate, ethyl cellulose acetate phthalate, hydroxypropyl celluloseacetate phthalate, hydroxypropyl methyl cellulose acetate phthalate,hydroxypropyl cellulose acetate phthalate succinate, hydroxypropylmethyl cellulose acetate succinate phthalate, hydroxypropyl methylcellulose succinate phthalate, cellulose propionate phthalate,hydroxypropyl cellulose butyrate phthalate, cellulose acetatetrimellitate, methyl cellulose acetate trimellitate, ethyl celluloseacetate trimellitate, hydroxypropyl cellulose acetate trimellitate,hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropylcellulose acetate trimellitate succinate, cellulose propionatetrimellitate, cellulose butyrate trimellitate, cellulose acetateterephthalate, cellulose acetate isophthalate, cellulose acetatepyridinedicarboxylate, salicylic acid cellulose acetate, hydroxypropylsalicylic acid cellulose acetate, ethylbenzoic acid cellulose acetate,hydroxypropyl ethylbenzoic acid cellulose acetate, ethyl phthalic acidcellulose acetate, ethyl nicotinic acid cellulose acetate, ethylpicolinic acid cellulose acetate, carboxymethyl ethyl cellulose, andmixtures thereof.
 13. The unitary dosage form of claim 8 wherein saidneutralized acidic polymer is a neutralized form of a polymer selectedfrom the group consisting of hydroxypropyl methyl cellulose acetatesuccinate, hydroxypropyl methyl cellulose phthalate, cellulose acetatephthalate, cellulose acetate trimellitate, carboxymethyl ethylcellulose, and mixtures thereof.
 14. The unitary dosage form of claim 8wherein said neutralized acidic polymer is a neutralized form of apolymer selected from the group consisting of carboxylic acidfunctionalized vinyl polymers, carboxylic acid functionalizedpolymethacrylates, carboxylic acid functionalized polyacrylates, andmixtures thereof.
 15. The unitary dosage form of claim 8 wherein saidneutralized acidic polymer has a glass transition temperature of atleast 40° C.
 16. The unitary dosage form of claim 8 wherein saidneutralized acidic polymer is ionically crosslinked.
 17. The unitarydosage form of claim 8 further comprising an excipient selected from thegroup consisting of a base and a buffer.
 18. The unitary dosage form ofclaim 1 wherein said dosage form provides an improvement in the maximumconcentration of said cholesteryl ester transfer protein inhibitor in ause environment of at least 1.25 fold relative to a control compositionconsisting essentially of said cholesteryl ester transfer proteininhibitor in crystalline form alone.
 19. The unitary dosage form ofclaim 1 wherein said dosage form provides in a use environment an areaunder the concentration of said cholesteryl ester transfer proteininhibitor versus time curve, for any period of at least 90 minutesbetween the time of introduction into the use environment, and about 270minutes following introduction to the use environment that is at least2-fold that of a control composition consisting essentially of saidcholesteryl ester transfer protein inhibitor in crystalline form alone.20. The unitary dosage form of claim 1 wherein said dosage form providesan improvement in the relative bioavailability of said cholesteryl estertransfer protein inhibitor in a use environment of at least 1.25 foldrelative to a control composition consisting essentially of saidcholesteryl ester transfer protein inhibitor crystalline form alone. 21.The unitary dosage form of claim 1 further comprising a disintegrant.22. The unitary dosage form of claim 1 further comprising a porosigen.23. The unitary dosage form of claim 1 wherein said HMG-CoA reductaseinhibitor is selected from the group consisting of fluvastatin,lovastatin, pravastatin, atorvastatin, simvastatin, rivastatin,mevastatin, velostatin, compactin, dalvastatin, fluindostatin,rosuvastatin, pitivastatin, dihydrocompactin, cerivastatin, andpharmaceutically acceptable forms thereof.
 24. The unitary dosage formof claim 1 wherein said HMG-CoA reductase inhibitor is selected from thegroup consisting of atorvastatin, the cyclized lactone form ofatorvastatin, a 2-hydroxy, 3-hydroxy or 4-hydroxy derivative of saidcompounds, and pharmaceutically acceptable forms thereof.
 25. Theunitary dosage form of claim 1 wherein said cholesteryl ester transferprotein inhibitor has a minimum aqueous solubility over the pH range offrom 1 to 8 of less than about 10 μ/ml.
 26. The unitary dosage form ofclaim 1 wherein said cholesteryl ester transfer protein inhibitor has adose to aqueous solubility ratio of at least 1000 ml.
 27. The unitarydosage form of claim 1 wherein said cholesteryl ester transfer proteininhibitor has a Log P value of at least 4.0.
 28. The unitary dosage formof claim 1 wherein said cholesteryl ester transfer protein inhibitor isselected from the group consisting of the compounds of Formula I,Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII,Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, FormulaXIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII,and Formula XIX.
 29. The unitary dosage form of claim 28 wherein saidcholesteryl ester transfer protein inhibitor is a compound of FormulaIV.
 30. The unitary dosage form of claim 1 wherein said cholesterylester transfer protein inhibitor is selected from the group consistingof[2R,4S]-4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester,[2R,4S]-4-[3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester and[2R,4S]-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester,[2R,4S]-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester, and(2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol.31. The unitary dosage form of claim 1 wherein said dosage form isselected from the group consisting of a tablet, a caplet, a pill, acapsule, and a powder.
 32. The unitary dosage form of claim 31 whereinsaid dosage form comprises a capsule.
 33. The unitary dosage form ofclaim 32 wherein said dosage form is in a form selected from the groupconsisting of a plurality of granules, a compressed tablet, and aplurality of multiparticulates.
 34. The unitary dosage form of claim 33wherein said HMG-CoA reductase inhibitor is in a form selected from thegroup consisting of a plurality of granules, a compressed tablet, and aplurality of multiparticulates.
 35. The unitary dosage form of claim 1wherein said dosage form comprises a kit.
 36. The unitary dosage form ofclaim 37 wherein said kit is selected from the group consisting of adivided container and a divided foil packet.
 37. The unitary dosage formof claim 35 wherein said solid amorphous dispersion is in a formselected from the group consisting of a plurality of granules, acompressed tablet, and a plurality of multiparticulates.
 38. The unitarydosage form of claim 37 wherein said HMG-CoA reductase inhibitor is in aform selected from the group consisting of a plurality of granules, acompressed tablet, and a plurality of multiparticulates.
 39. The unitarydosage form of any one of claims 1-38 wherein said cholesteryl estertransfer protein inhibitor is torcetrapib and said HMG-CoA reductaseinhibitor is selected from the group consisting of atorvastatin andpharmaceutically acceptable forms thereof.
 40. The unitary dosage formof claim 39 wherein said dosage form comprises 1 to 1000 mg of saidcholesteryl ester transfer protein inhibitor and 1 to 160 mg of saidHMG-CoA reductase inhibitor.
 41. A method for forming a unitary dosageform comprising: (a) forming a solid amorphous dispersion comprising acholesteryl ester transfer protein inhibitor and aconcentration-enhancing polymer; and (b) combining said solid amorphousdispersion with an HMG-CoA reductase inhibitor to form said unitarydosage form; wherein said concentration-enhancing polymer is at leastone of a neutral polymer and a neutralized acidic polymer.
 42. Themethod of claim 41 wherein said step (b) further comprises the step offorming a plurality of granules comprising said solid amorphousdispersion.
 43. The method of claim 42 further comprising the step offorming an HMG-CoA reductase inhibitor composition, and then mixing saidHMG-CoA reductase inhibitor composition with said plurality of granules.44. The method of claim 41 wherein said step (b) further comprises thestep of forming a plurality of granules comprising said HMG-CoAreductase inhibitor.
 45. The method of claim 44 further comprising thestep of forming a cholesteryl ester transfer protein inhibitorcomposition comprising said solid amorphous dispersion, and then mixingsaid plurality of granules with said cholesteryl ester transfer proteininhibitor composition.
 46. The method of claim 41 further comprising thestep of neutralizing an acidic polymer to form said neutralized acidicpolymer.
 47. The method of claim 46 wherein said neutralized acidicpolymer is formed by the steps of (1) dissolving said acidic polymer ina solvent to form a solution and (2) adding a base to said solution. 48.The method of claim 46 wherein said cholesteryl ester transfer proteininhibitor and said acidic polymer are both dissolved in a common solventto form a solution, and said solvent is removed from said solution toform said solid amorphous dispersion.
 49. The method of claim 48,further comprising the step of adding a base to said solution.
 50. Themethod of claim 46 wherein said acidic polymer is neutralized prior tobeing combined with said cholesteryl ester transfer protein inhibitor.51. The method of claim 46 wherein said acidic polymer is combined withsaid cholesteryl ester transfer protein inhibitor prior to said step ofneutralizing said acidic polymer.
 52. The method of claim 51 whereinsaid acidic polymer and said cholesteryl ester transfer proteininhibitor are formed into an acidic solid amorphous dispersion, and saidacidic solid amorphous dispersion is then combined with at least one ofa base and a buffer to form said neutralized acidic polymer.
 53. Theproduct of the method of any one of claims 41-52.